Patent Application 15769931 - METHODS FOR TREATING NEURODEGENERATIVE DISEASES

Title: METHODS FOR TREATING NEURODEGENERATIVE DISEASES USING GENE THERAPY TO DELAY DISEASE ONSET AND PROGRESSION WHILE PROVIDING COGNITIVE PROTECTION

Application Information

Invention Title: METHODS FOR TREATING NEURODEGENERATIVE DISEASES USING GENE THERAPY TO DELAY DISEASE ONSET AND PROGRESSION WHILE PROVIDING COGNITIVE PROTECTION
Application Number: 15769931
Submission Date: 2025-04-10T00:00:00.000Z
Effective Filing Date: 2018-04-20T00:00:00.000Z
Filing Date: 2018-04-20T00:00:00.000Z
National Class: 424
National Sub-Class: 093200
Examiner Employee Number: 82359
Art Unit: 1633
Tech Center: 1600

Rejection Summary

102 Rejections: 0
103 Rejections: 3

Cited Patents

The following patents were cited in the rejection:

US 0195801🔗

Office Action Text

DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .

Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/11/24 has been entered.
Claims 1, 6-8, 10-15, 19-22, 24-28, 30-31, 36, 38 and 58 are pending and subject to prosecution. Claims 1, 10 and 38 are amended. Claims 4 and 37 are cancelled.

Priority
The instant Application, filed 4/20/2018, is a 371 National Stage Application of PCT/US16/58484, filed 10/26/2016, which claims priority to US Provisional Application No. 62/245,824, filed 10/23/2015. Thus, the earliest possible priority for the instant Application is 10/23/2015.

Claims
Independent claim 1 is directed to a method of treating a lysosomal storage disease by administering an adeno-associated viral vector encoding a lysosomal hydrolase, wherein a first immunosuppressant is cyclosporine and second immunosuppressant is mycophenolate or mycophenolate mofetil (MMF) are administered, and wherein at the first and second immunosuppressants are administered prior to the administration of the AAV vector.
The claim has been amended to require wherein:
the AAV particles comprise an AAV2 capsid protein;
wherein the first and second immunosuppressants are administered prior to administration of the AAV particles;
changed the phrase “wherein a neutralizing antibody response in said mammal is reduced by administration of said first immunosuppressive agent” to wherein the response is “inhibited;”
to delete the functional requirement “wherein neutralizing antibodies are not detected in cerebral spinal fluid in the treated mammal for at least 30, 60, 90 or 120 days after administration of said AAV particles”.

Applicant asserts that the amendment from “reduced” to “inhibited” encompasses that there can be some neutralizing antibody response, not a complete lack thereof, based on the disclosure at [0217]. The examiner notes that nothing in the specification discloses “reduced” is defined any differently than “inhibited,” nor is “reduced” defined as wherein there is no neutralizing antibody response, but “inhibited” can comprise “some” neutralizing antibody response. Thus, the broadest reasonable interpretation allows “reduced” and “inhibited” as equal terms, which can comprise some, or no, neutralizing antibody response, and does not aid in changing the scope of the claim.

It is further noted that the previous rejection of record, including over independent claim 1, specifically considered wherein 1) the AAV particles comprised AAV2 capsid, 2) the first and second immunosuppressants were administered before administering the recombinant AAV; and 3) wherein the methodology results in an inhibited/reduced neutralizing antibody response.

Independent claim 1 is directed to:
“A method of treating a mammal having a lysosomal storage disease (LSD) associated with tripeptidylpeptidase 1 (TPP1) insufficiency, said method comprising the steps:
(a) administering to the brain or spinal cord of a mammal a plurality of adeno-associated virus (AAV) particles at a dose of about 1 x 108 to about 1 x 1015 vector genomes per kilogram (vg/kb), said AAV particles
(i) comprising an AAV2 capsid protein and a nucleic acid inserted between a pair of AAV inverted
terminal repeats (ITRs), said nucleic acid encoding a polypeptide comprising TPP1 or a TPP1 pro-enzyme, and
(ii) being capable of transducing cells of said mammal and proteins expression of said polypeptide; and
(b) administering to said mammal a first immunosuppressive agent, wherein said first immunosuppressive agent is cyclosporine and wherein said cyclosporine is administered at a dosage of about 5-20 milligram per kilogram (mg/kg) twice a day for a period of at least 3 months, and a second immunosuppressive agent, wherein said second immunosuppressive agent is either mycophenolate or mycophenolate mofetil (MMF),

wherein said first immunosuppressive agent and said second immunosuppressive agent are administered to said mammal prior to administration of said AAV particles, and

wherein a neutralizing antibody response in said mammal is inhibited by administration of said first immunosuppressive agent and said second immunosuppressive agent,

and

wherein said mammal is a human.”

The instant specification teaches neutralizing antibodies encompass neutralizing antibodies to AAV or to the lysosomal enzyme itself (paragraph [0031]).

RESPONSE TO ARGUMENTS
Applicant’s arguments with regard to the 103 rejection of claims as obvious over Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao have been fully considered but are not persuasive. The Examiner notes that Applicant has amended the claims to remove the functional limitation of “wherein neutralizing antibodies are not detected in cerebral spinal fluid in the treated mammal for at least 30, 60, 90 or 120 days after administration of said AAV particles” that was previously recited in pending claim 1 (and previously cited in claim 33). While Applicant has amended claim 1 to require wherein 1) the AAV particle is AAV2; 2) that the cyclosporine and MMF are administered before the AAV particles; and a neutralizing antibody response is “inhibited” instead of “reduced” by administration of the first and second immunosuppressants.
As noted in the Non-Final Action of 08/09/2023, the Examiner noted that advancement of prosecution may occur with amendment to the independent claims to include the functional limitations of 8, 25-28, OR 33, AND provide evidence in the form of a declaration to show that the claimed functional limitations were not predictable in humans, that the working examples appear to be limited to dogs.
In response to the Non-Final Action of 08/09/2023, applicant amended claim 1 to require the functional limitations of claim 33 (“wherein neutralizing antibodies are not detected in cerebral spinal fluid in the treated mammal for at least 30, 60, 90 or 120 days after administration of said AAV particles”), but provided no declaration comprising evidence (Reply dated 02/07/2024). Applicant argued that none of the cited references taught the claim as amended, and none of the cited references cured the deficiencies of Davidson because the art was unpredictable with regard to the generation of neutralizing antibodies following administration of immunosuppressant therapy.
In the Final Rejection dated 05/09/2024, the Examiner noted applicant’s amendments and arguments were not sufficient to overcome the rejection of record, and noted Applicant provided no evidence to support Applicant’s position, in the form of a declaration, or even evidence from the pending specification, to show the claimed functional effect was surprising. As an attempt to advance prosecution, the Examiner reviewed the specification for evidence that would support applicant’s assertion. The Examiner noted the limited working examples were not commensurate with regard to the pending claims, as the examples used at least a dog model, a specific AAV dosage, a specific AAV capsid and vector, a specific timing regiment of administering cyclosporine and MMF. The examiner noted that a lack of anti-TPP1 antibodies was only identified in a single dog (DC018), who had received both cyclosporine and MMF prior to AAV2 vectors and the data. The Examiner noted that the single working example was not sufficient to overcome the rejection in light of the requirements that the showing of unexpected results were not commensurate with regard to the pending claims according to MPEP 716,02(d) (see, Final Rejection mailed 05/09/2024 at pages 20-21).
In response to that Final Rejection, Applicant has, as noted above, amended claim 1 to remove the functional limitation of “wherein neutralizing antibodies are not detected in cerebral spinal fluid in the treated mammal for at least 30, 60, 90 or 120 days after administration of said AAV particles” while inserting the requirement wherein 1) the AAV particle is AAV2; 2) that the cyclosporine and MMF are administered before the AAV particles, and that the substitution of wherein a neutralizing antibody response is “inhibited” instead of “reduced”.
Applicant argues the amendment from a “reduced” to “inhibited” neutralizing antibody response is interpreted such that there can be some amount of neutralizing antibody response following the claimed method, not that is a complete lack of neutralizing antibody response.
Applicant argues evidence from the present specification show that cyclosporine and MMF were co-administered to diseased dogs, which resulted in long-term TPP1 expression and dramatic improvement of numerous clinical symptoms of the LSD, and as much as two-fold lifespan extension in the diseased dogs (FIGs 7E, 8A-8G, 9, 16 and paragraphs [0183]-[0185] and [0194] of the published PCT). Applicant argues the “robust and sustained” TPP1 activity lasted more than 57 weeks, in dogs where both immunosuppressants were administered prior to AAV particle administration (paragraph [0182] and FIGs. 7E and 7F). Applicant argues the evidence from the specification, along with the amendments to the claims (A: wherein a neutralizing antibody response is “inhibited” instead of “reduced” by administration of the first B) and second immunosuppressants before administering the AAV; and C) wherein the AAV capsid is AAV2) is sufficient to show unexpected results and capable of overcome the rejection of record.
Applicant further argues the art was unpredictable. Applicant argues one of skill in the art 1) would have expected no benefit or even an increase in neutralizing antibodies when considering the data in Jiang; 2) which contradicts Tardieu showing that administration of two immunosuppressants were effective in inhibiting neutralizing antibody response; and 3) Ferreira’s showing that a treatment-emergent antibody response was not always present.
The Examiner is not persuaded. The amendments to the claims have broadened the functional result of practicing the claimed invention. By removing the requirement of “wherein neutralizing antibodies are not detected in cerebral spinal fluid in the treated mammal for at least 30, 60, 90 or 120 days after administration of said AAV particles” the claim no longer requires any result other than a neutralizing antibody response is “inhibited.” However, with regard to Applicant’s assertion that the amendment from “reduced” to “inhibited” encompasses that there can be some neutralizing antibody response, based on the disclosure at [0217] is not persuasive. The examiner notes that nothing in the specification discloses “reduced” is defined any differently than “inhibited,” nor is “reduced” defined as wherein there is no neutralizing antibody response, but “inhibited” can comprise “some” neutralizing antibody response. Thus, the broadest reasonable interpretation allows “reduced” and “inhibited” as equal terms, which can comprise some, or no, neutralizing antibody response, and does not aid in changing the scope of the claim.
When considering the working examples of the specification as providing the evidence of surprising results that are recited in the claim, the Examiner is not persuaded. As noted above, the claim only requires that a neutralizing antibody response is “inhibited.” The amendment to encompass “some” neutralizing antibody response rather than a complete lack (for at least 30 days) of neutralizing antibody response appears to have been done in an attempt to encompass more of the working examples by the pending claim. There are 3 dogs that are encompassed by the pending claims that are encompassed in the working examples (DC018, DC109 and DC020). These dogs were administered 10 mg/kg of cyclosporine twice daily by mouth, one to two weeks prior to gene therapy vector administration, wherein the dose was gradually tapered after two months to one daily for the remainder of the study (paragraphs [0173], [0199] published specification). The dogs were also administered 10-20 mg/kg daily by mouth of MMF daily, starting 5 days before gene therapy vector administration, and tapered after 2 to several months (paragraphs [0173], [0199]). The specification states TPP1 activity and “NAb levels” were measured in dogs that were given immunosuppression treatment: at day -5 relative to vector infusion (FIGS.7E and 7F; DC019 shows 0.3 pmol/mg protein, which is 100% of normal) (paragraph [0053]).
The inactivating antibody response in 7F is performed by incubating purified TPP1 proenzyme with serial dilutions of CSF or serum collected from rAAV.caTPP1 treated CLN2-/- dogs, and then the mixture applied to Cln2 -/- mouse embryonic fibroblasts.

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The examiner notes that no data is provided which presents any quantified anti-TPP1 Nab titers. Rather, when “Uptake of TPP1” is less than 100%, one assumes that any lack of TPP1 activity is a direct result of neutralizing antibodies present. It is unclear how, using the data from FIG 7F, one can conclude the results of the methodology show “an inhibited neutralizing antibody response”? The data only shows “specific” time points wherein a single data set was calculated once for each dog. And, there appears to be quite a bit of variability along the time line for each individual dog. For example, at day 20, DC018 shows about 100% uptake, but at day 40 there is a reduction of uptake. At day 20, DC019 shows about 100% uptake, but at day 60 there is a reduction of uptake. At day 20, DC020 shows above 100% uptake, but at day 300 very little uptake. Thus, there would appear to be an increase in neutralizing antibodies at those later times relative to day 20. There is no discussion by Applicant how this data represents “an inhibited neutralizing antibody response” or how that data is surprising. The burden is on Applicant to articulate why the data in 7E is surprising MPEP 716.02(b).
Applicant’s generalized arguments that additional data from the specification, which resulted in long-term TPP1 expression and dramatic improvement of numerous clinical symptoms of the LSD, and as much as two-fold lifespan extension in the diseased dogs; and wherein the “robust and sustained” TPP1 activity lasted more than 57 weeks, in dogs where both immunosuppressants were administered prior to AAV particle administration are evidence of unexpected results are not persuasive. There is no discussion by Applicant how this data represents unexpected results. The burden is on Applicant to articulate why the data in specification is surprising MPEP 716.02(b).
The results of the specification appear to show that expression of TPP1 enzyme in a CLN2-/- model improves clinical symptoms in the dogs. However, these results are to be expected. As taught by Davidson of record in the 103 rejection below, TPP1 enzyme delivery to LINCL mice via CSF shows attenuated neuropathology and decreased resting tremor relative to vehicle-treated mice was known in the art (page 29). Davidson also exemplifies AAV2-TPP1 administered to the brain resulted in increased levels and activity of TPP1 in the brain of treated animals (FIGs 3and 4). Davidson shows stereotactic delivery of the AAV-TPP1 to LINCL dogs showed detectable levels of TPP1 in various tissues of the brain, significant attenuation of brain atrophy, increased longevity and improved cognitive function (page 31).
With regard to Applicant’s assertion that the working examples show “robust and sustained” TPP1 activity lasted more than 57 weeks as evidence of unexpected results, the Examiner is not persuaded. FIG 7E shows TPP1 activity over 400 days for the three dogs (DC018, DC109 and DC020) encompassed by the claims:

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Initially, the Examiner notes the specification fails to define “robust and sustained” TPP1 activity. So, it is unclear how one would determine what “robust and sustained” TPP1 activity is. The Examiner notes that the TPP1 activity in the three dogs from day 0 to day 400 varies greatly. From 0 to over 100, depending on the dog and the day. Which data set(s) represent “robust and sustained” expression? Anything more than 0? Further, looking at FIG 7E, there is only one dog who shows any TPP1 activity at 400 days (57 weeks).
The showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. MPEP 716.02(d). Here, the working example’s showing of three dogs and its single treatment regimen achieving a reduced neutralizing antibody response, improved clinical symptoms, increased longevity, and “robust and sustained” TPP1 activity of at least 57 weeks is not commensurate in scope with the claimed invention. The Examiner notes that no functional result is recited in the claim, other than “inhibited” neutralizing antibody response. The methodology utilized in the working example is narrower than the methodology claims. The methodology administers a specific dosage of AAV2-TPP1 vectors, a specific dose of cyclosporine at specific days before (and after) AAV particle administration, a specific dose of MMF at specific days before (and after) AAV particle administration.
Further, the Examiner notes that the 3 dogs treated exhibited wide variability of TPP1 expression/ activity/and neutralizing antibody response over the course of treatment, and all three did not exhibit the asserted surprising results similarly. The single experiment, using 3 dogs, cannot support a finding of surprising results of claim 1 or demonstrated in the specification as asserted.
With regard to Applicant’s assertion that the art was unpredictable with regard to the generation of neutralizing antibodies in response to administering immunosuppressant therapy, when considering the disclosures of Jaing, Tardieu, and Ferreira, and their allegedly opposite results following administering two immunosuppressants in an AAV methodology. The examiner cannot agree.
Applicant argues one of skill in the art would have expected no benefit or even an increase in neutralizing antibodies following the administration of two immunosuppressants when considering the data in Jiang et al. The examiner notes that the methodology of Jiang is wholly different than currently claimed, which requires administration of AAV2 vectors to the brain or spinal cord, and administering cyclosporine and MMF as the immunosuppressants. The results seen in the instant specification are from an even narrower methodology, using a specific dosage of AAV2-TPP1 vectors, a specific dose of cyclosporine at specific days before (and after) AAV particle administration (10 mg/kg of cyclosporine twice daily by mouth, one to two weeks prior to gene therapy vector administration, wherein the dose was gradually tapered after two months to one daily for the remainder of the study), a specific dose of MMF at specific days before (and after) AAV particle administration (10-20 mg/kg daily by mouth of MMF daily, starting 5 days before gene therapy vector administration, and tapered after 2 to several months).
The location of administration of the AAV, the type of immunosuppressants used, and the course of administration of the immunosuppressants in Jiang cannot be fairly compared to the scope of the pending claims, or the results seen in the present specification. While the examiner agrees Jiang administers two immunosuppressants prior to AAV administration, Jiang administers an AAV8 vector via direct injection into the hepatic artery of nonhuman primates (page 3323). Jiang uses a transient immunosuppression protocol, administering MMF and tacrolimus from only from day -3 to day 45 of the experiment.
With regard to Applicant’s assertion that Tardieu shows that administration of two immunosuppressants is effective in inhibiting neutralizing antibody response the examiner agrees. The examiner also notes that the AAV vectors of Tardieu are administered directly to the brain and a regiment of tacrolimus and MMF were administered -15 days before AAV administration, and maintained for 8 weeks or throughout 1 year of follow-up. Thus, the results in Tardieu, whose methodology is more closely aligned with the methodology of the pending claims, support the predictability use of two immunosuppressants in an AAV methodology as claimed.
With regard to Applicant’s assertion that because Ferreira shows that a treatment-emergent antibody response was not always present, one would not have thought it necessary to administer any immunosuppressant agent, the examiner cannot agree. The fact that Ferreira discloses that treatment emergent inactivating antibodies are not always present does not undermine the predictability of the pending claims. Like Jiang, the methodology of Ferreira is wholly different than currently claimed. Ferreira discloses the AAV1-LPL vectors were administered via intra-muscular injection and the immunosuppressants were administered 30 minutes earlier than AAV administration, and for a period of 12 weeks (CT-AMT-011-02, page 3).
The skilled artisan would not consider the specific results of Jiang or Ferreira comparable with regard to the pending claims because their specific methodologies are so different from the pending claims. Ferreira states the data therein should be considered in the context of the growing body of studies showing that the immune responses against AAV capsid proteins can vary widely and amongst others are influenced by the target organ, route of delivery, and dosing schedule (page 13). Thus, a skilled artisan would not consider the specific data of Ferreira comparable to the methodology of the pending claims, nor to Jiang, nor to the disclosure of Tardieu. However, in light of Ferreira, the skilled artisan would consider the results in Tardieu relatable to the pending claims, as the methodology Tardieu is closely aligned with the methodology of the pending claims.
Taken together, the Examiner disagrees that the evidence asserted is unexpected, and even if it were, which the Examiner does not concede, the evidence is not commensurate with the scope of the pending claims. The Examiner also disagrees that the prior art is unpredictable with respect to the pending claims.
Applicant further reiterates the previous arguments over Davidson, Worgall, Silva, Gao, Vogel and Lobel, of record 02/07/2024. These arguments are found non-persuasive, for the reasons stated in the office action 05/09/2024.

Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.

The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 6-8, 10-14, 19-22, 24-28, 30-31, 36 and 38 remain rejected under 35 U.S.C. 103 as obvious over WO2012/135857 to Davidson (of record), Worgall et al. Treatment of Late Infantile Neuronal Ceroid Lipofuscinosis by CNS Administration of a Serotype 2 Adeno-Associated Virus Expressing CLN2 cDNA. Human Gene Therapy, 2008. 19:463-474, Tardieu et al. Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial. Human Gene Therapy, 2014. 25:506-516, Ferreira et al. Immune Responses to AAV-vectors, the Glybera Example from Bench to Bedside. Frontiers in Immunology, 2014. 5. Article 82, 15 pages, Silva et al. One Year Results with Extended-Release Tacrolimus/MMF, Tacrolimus/MMF and Cyclosporine/MMF in De Novo Kidney Transplant Recipients. American Journal of Transplantation, 2007. 7:595-608, and US Patent Application No. 2013/0195801 to Gao (of record). This rejection is modified in response to Applicant’s amendments to the claims.
With regard to claim 1, Davidson discloses lysosomal storage diseases are generally caused by a lysosomal hydrolase enzyme deficiency (page 29). Davidson discloses methods of treating lysosomal storage diseases in a mammal comprising administering to the mammal, in vivo, an AAV vector encoding the missing lysosomal hydrolase enzyme to the brain or spinal cord (CSF) of the mammal, wherein the mammal is a human (page 3, page 4, page 8-9, pages 11-15, pages 18-19, page 23, Example 1; Claims 1-2, 8-9, 11-16). Davidson discloses the lysosomal storage diseases that can be treated by replacing the lysosomal enzyme include late infantile ceroid lipofuscinoses (LINCL), MPS VII and Sanfilopo A disease (claims 1-2, 8-9, 11-15; page 3, 12, 14). Davidson discloses the lysosomal hydrolases are encoded between two inverted terminal repeat sequences of the AAV (page 3; page 7-8, Claims 1-2). Davidson discloses the AAV vector is an AAV2 particle (Pages 29-31).
Davidson discloses treatment of lysosomal storage disorders LINCL or MPS VII, in in vivo animal models, is treated by encoding TPP1 or beta-glucuronidase, respectively, on AAV vectors, and administering to the brain to treat LINCL or MPS VII (pages 29-31).
Davidson discloses the AAV encoding TPP1 particles are administered to the brain of a TPP1 deficient dog model, where the AAV particles express TPP1 in vivo (examples). Davidson shows that cognitive abilities improved, brain atrophy was reduced, and longevity was increased in animals treated with AAV vectors encoding TPP1 compared to controls (page 31; FIG 5). Davidson shows the AAV encoding beta-glucuronidase particles are administered to the brain of MPS VII mice model, where the AAV particles express beta-glucuronidase in vivo (examples, page 30). MPS VII treated with AAV vectors encoding beta-glucuronidase showed improvements in impaired conditioned fear responses and context discrimination (page 30).
Davidson discloses the therapeutically effective number of viral particles administered is determined by the skilled artisan, depending on viral vector, the subject, the treatment regimen (page 25).
However, Davidson does not disclose wherein the plurality of adeno-associated virus (AAV) particles at a dose of about 1 x 108 to about 1 x 1015 vector genomes per kilogram (vg/kb), or
the method further includes administering to said mammal a first immunosuppressive agent, wherein said first immunosuppressive agent is cyclosporine and wherein said cyclosporine is administered at a dosage of about 5-20 milligram per kilogram (mg/kg) twice a day for a period of at least 3 months, and a second immunosuppressive agent, wherein said second immunosuppressive agent is either mycophenolate or mycophenolate mofetil (MMF),
wherein the said first immunosuppressive agent and said second immunosuppressive agent are administered to said mammal prior to administration of said AAV particles,
and wherein a neutralizing antibody response in said mammal is inhibited by administration of said first immunosuppressive agent and said second immunosuppressive agent, as required by instant claim 1.
Worgall discloses methods of treating lysosomal storage disease associated with TPP1 insufficiency in human children, comprising administering to the brain or spinal cord an AAV vector encoding human TPP1 (CLN2) (Abstract; page 464). Worgall discloses the AAV-hCLN2 vectors are administered at a dose of 1.8 to 3.2 x 1012 particles (page 464). Following administration of the AAV-hCLN2 vectors, subjects generated neutralizing antibody titers for up to 18 months post therapy (page 467-468).
Tardieu discloses methods of treating lysosomal storage disease Mucopolysaccharidosis Type IIIV (Sanfilippo type A) in human children, comprising administering to the brain a plurality of AAV particles encoding N-sulfoglycosamine sulfohydrolase (SGSH) and sulfatase-modifying factor (SUMF1), wherein the method further comprises administration of an immunosuppressant regimen (abstract, Protocol, page 513). Tardieu discloses the viral particles are administered as a dose of 7.2 x 1011 particles to the brain (abstract, page 509). Tardieu discloses the immunosuppressant regimen comprises administering a first immunosuppressant of tacrolimus, and a second immunosuppressant of mycophenolate mofetil, wherein the tacrolimus and mycophenolate are administered 14 days before administration of the AAV viral particles, at doses of 0.2 mg/kg/day for tacrolimus, and 1200 mg/m2/day for mycophenolate (Abstract, pages 508-509). Tacrolimus was administered daily for at least 3 months (page 509).
Tardieu discloses the inclusion of the immunosuppressant regiment was based on pre-clinical studies in animals, wherein immunosuppression prevented neuroinflammation and elimination of transduced cells, and the high frequency of anti-vector neutralizing antibody production in previous intracerebral gene therapy trials in humans, consistent with antigen presentation outside the brain and a risk of the transfected cells being eliminated by the host immune cells (page 507, page 514, first column). Tardieu shows that no neutralizing antibodies were detected in the serum of the children 12 months after administration (page 514).
Ferreira discloses methods of immunosuppression before or concomitant with AAV administration are known, including administration of Cyclosporin A and MMF, or tacrolimus and MMF (page 11, first column; page 13, first column). Ferreira discloses the doses for the immunosuppressants are based on doses used for transplant rejection (page 10, second column). Ferreira discloses dosages of AVV vectors to humans can be provided as vector genomes/kilogram of body weight (page 3, FIG 1, FIG 5).
Silva discloses clinically effective immunosuppression therapies in de novo kidney transplant recipients, comprising the administration of tacrolimus (once a day) and MMF, tacrolimus (twice a day) and MMF, and cyclosporine A (twice a day) with MMF (abstract). Silva discloses the clinically effective doses of cyclosporine A include 5 milligram/kg, twice per day (page 596, first column). Silva discloses the cyclosporine A and MMF immunosuppressant therapy resulted in 97.6% and 95.7% graft survival at one year (Abstract). Silva discloses the cyclosporine A and MMF immunosuppressant therapy efficacy is similar to once a day administration of tacrolimus and MMF, which shows 98.6% and 96.7% graft survival at one year (Abstract).
Gao discloses methods of administering AAV particles to the CNS for gene therapy (Abstract). Gao discloses the AAV particles can encode therapeutic transgenes, including those to treat lysosomal storage diseases (paragraph [0069], [0097]). Gao discloses the route of administration includes administering directly to the spine or brain via injection (paragraphs [0066]-[0067]). Gao discloses delivery to the CNS includes wherein the AAV particles contact, transduce and express the transgene in endothelial cells (paragraph [0236]). Gao discloses the dosing required to achieve a desired or therapeutic effect can be provided as vector genomes/kilogram of body weight, and is determined by route of administration, level of gene expression required, specific disease, stability of the gene product. Gao “one of skill in the art can readily determine a rAAV virion dose range to treat a subject having a particular disease or disorder based on the aforementioned factors, as well as other factors that are known in the art” (paragraph [0104]). Gao discloses in some cases the AAV are administered at a dose of 1010-1015 viral genomes /kg (paragraph [0104]).
It would have been obvious to combine the disclosure of Davidson, on methods of administrating AAV vectors encoding TPP1 to the brain or spinal cord to a mammal, including humans, further with the disclosures of Worgall, Tardieu, Ferreira and Silva. Davidson does not reduce the methodology to practice in humans. Worgall shows administration of AAV vectors encoding TPP1 to the brain or spinal cord of humans is capable of transducing and expressing TPP1 in human brains, with a therapeutically effective dose of AAV-TPP1 particles. Worgall shows subjects generated anti-AAV neutralizing antibody titers for up to 18 months post therapy. A skilled artisan would have been motivated to include an immunosuppressant regimen, comprising a first and second immunosuppressant administered before the AAV-TPP1 vector, to the methods of Davidson because Tardieu shows an immunosuppressant regimen comprising a first and second immunosuppressant administered before administration of a AAV-vector to the brain or spinal cord of human patients, encoding an enzyme to treat a different lysosomal disease, is capable of preventing generation of neutralizing anti-AAV antibodies in the serum. A skilled artisan would have recognized from the teachings of Tardieu the inclusion of an immunosuppressant protocol would be capable of inhibiting or preventing neutralizing antibody formation in treated humans. See, MPEP 2143 (I)(A) Combining prior art elements according to known methods to yield predictable results; (I)(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results.
With regard to the claimed requirement wherein the first immunosuppressant and the second immunosuppressant are cyclosporine and MMF, and wherein the cyclosporine is administered at a dosage of about 5-20 milligram per kilograms twice a day for at least 3 months, the claim is obvious from the cited art. Tardieu discloses immunosuppressant regimens comprising tacrolimus and MMF, and wherein the tacrolimus is administered at a dosage of about 0.2 mg/kg/day for tacrolimus for at least 3 months. The substitution of cyclosporine for tacrolimus is obvious because both are explicitly taught as being useful for immunosuppression regimens in AAV gene therapy protocols. Further, Ferreira discloses the doses for the immunosuppressants are based on doses used for transplant rejection, and Silva discloses cyclosporine A and MMF immunosuppressant therapy, wherein the cyclosporine is administered at a dose of about 5 mg/kg, has an efficacy comparable to tacrolimus and MMF in human kidney transplant patients. See, MPEP2143(I)(B) Simple substitution of one known element for another to obtain predictable results. Further, the selection of about 5-20 milligram per kilograms twice a day of cyclosporine is known from the immunosuppression protocol of kidney transplant patients of Silva, and Ferreira discloses immunosuppression protocols in AAV gene therapy are based on doses used for transplant rejection. The selection of a known material based on its suitability for its intended use supports a prima facie obviousness determination (see, MPEP 2144.07).
With regard to the claimed requirement wherein the AAV particles are administered at a dose of about 1 x 108 to about 1 x 1015 vector genomes per kilogram (vg/kb), it would have been obvious to combine Davidson further with the disclosures of Worgall, Ferreira and Gao. Davidson does not disclose the AAV particles are administered as a therapeutically effective amount of vg/kg. Rather, Davidson discloses the therapeutically effective number of viral particles administered is determined by the skilled artisan, depending on viral vector, the subject, the treatment regimen reduce the methodology to practice in humans. Worgall shows administration of AAV vectors encoding TPP1 to the brain or spinal cord of humans is capable of transducing and expressing TPP1 in human brains, wherein the therapeutically effective dose of 1.8 to 3.2 x 1012 AAV TPP1 particles. Ferreira discloses therapeutically effective amounts of AAV vectors administered to humans can be dosed as vg/kg. A skilled artisan would have looked to the disclosure of Gao on parameters of AAV delivery to CNS, including types of cells that can be transduced and dosages. See MPEP 2143 (I)(A) and (E): Combining prior art elements according to known methods to yield predictable results; "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success. In the instant case, all of the parameters are known in the art, just not in a single reference. In combination each element merely performs that same function as it does separately. Further, Goa provides a finite number of identified, predictable solutions for AAV expression and the dosages, and discloses that the skilled artisan can figure out effective amounts depending on need. Thus, a skilled artisan would have had a reasonable expectation of success in practicing the claimed invention as the claimed elements were known in the art of AAV delivery to the CNS at the time of the invention.
Taken together, a skilled artisan would have had a reasonable expectation of success in practicing the claimed invention, as administration of AAV vectors to the brain encoding TPP1 to treat liposomal storage disease is known (Davidson), the art teaches reduction to practice in humans results in the generation of neutralizing antibodies (Worgall), the art teaches the prevention of neutralizing antibodies to AAV administered to the brain can be accomplished by immunosuppressant regimens administered before AAV administration to the brain in other lysosomal storage disorders in humans (Tardieu), the art teaches an immunosuppressant regimen comprising administering a first immunosuppressant and MMF, wherein the first immunosuppressant is administered for at least three months is known (Tardieu), and the art teaches wherein immunosuppressant regimens of cyclosporine A and MMF are similarly as effective as tacrolimus and MMF in vivo in humans, at the claimed dosage.
With regard to claims 6-7, Davidson does not disclose an immunosuppressant regimen. The claims are obvious for the same reasons as stated above for claim 1. Tardieu discloses the immunosuppressant regimen comprises administering a first immunosuppressant of tacrolimus, and a second immunosuppressant of mycophenolate mofetil (Abstract, pages 508-509).
With regard to claim 10, Davidson does not disclose an immunosuppressant regimen. The claim is obvious for the same reasons as stated above for claim 1. Tardieu discloses the immunosuppressant regimen comprises administering a first immunosuppressant and a second immunosuppressant are administered 14 days before administration of the AAV viral particles (Abstract, pages 508-509). Thus, it would have been obvious to administer cyclosporine and MMF at the claimed about two weeks before AAV administration.
With regard to claims 11-14, 22 and 24, Davidson discloses the AAV vectors can be administered into the brain ventricles, or the CSF, or by contacting ependymal cells with the AAV particles, which are then transduced and secrete the TPP1 into the CSF (page 29-31).
With regard to claims 19-20, the claims are obvious for the same reasons as stated above for claim 1. Davidson does not reduce the methodology to practice in humans. Worgall shows administration of AAV vectors encoding TPP1 to the brain or spinal cord of human children is capable of transducing and expressing TPP1 in human brains, with a therapeutically effective dose of AAV-TPP1 particles (Abstract). Worgall shows the children treated including 3 and 4 year olds (Table 1).
With regard to claim 21, the claim is obvious for the same reasons as stated above for claim 1. Davidson discloses the lysosomal storage diseases that can be treated by replacing the lysosomal enzyme include late infantile ceroid lipofuscinoses (LINCL) and Sanfilopo A disease (claims 1-2, 8-9, 11-15; page 3, 12, 14).
With regard to claim 30, the claim requires wherein the cyclosporine (the first immunosuppressant) dose is reduced about 1-2 months after administration, Davidson does not disclose an immunosuppressant regimen. However, Tardieu discloses the immunosuppressant regimen comprises administering a first immunosuppressant of tacrolimus, and a second immunosuppressant of mycophenolate mofetil, wherein the tacrolimus is administered initially at a doses of 0.2 mg/kg/day for 3 months, and then is reduced (Abstract, pages 508-509). Thus, the reduction of the cyclosporine after about 1-2 months is obvious from the combination of the cited art.
With regard to claim 31, Davidson does not disclose an immunosuppressant regimen. The claim is obvious for the same reasons as stated above for claim 1. Tardieu discloses the immunosuppressant regimen comprises administering a first immunosuppressant of tacrolimus, and a second immunosuppressant of mycophenolate mofetil, wherein the mycophenolate is administered at 1200 mg/m2/day for mycophenolate (Abstract, pages 508-509).
With regard to claims 36, Davidson shows expression of recombinant enzyme in the cerebellum (page 30-31).
With regard to claim 38, Davidson discloses the AAV vectors comprise AAV2 or AAV4 ITRs (Page 31). Worgall discloses the AAV-TPP1 vectors comprise AAV2 vectors with AAV2 ITRs (page 464-465).
With regard to claims 8 and 25-28, the claims require wherein “the onset of a symptom of the LSD” or “the onset of a loss of cognitive function” or the lifespan is extended delayed by 5-100 days when both immunosuppressants are administered, compared to a method wherein the first immunosuppressant is not administered, etc. Thus, the claims comprise contingent limitations that the treated mammals (amended to humans) exhibit functional effects of the methodology practiced in the active steps of claim 1. The claims do not require not require any additional active steps further than that already performed in claim 1. MPEP 2111.04. Thus, because Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao obvious the method steps of claim 1, functional effects of the claims are rendered obvious. The claimed improved effects are likewise predictable, as Davidson shows that cognitive abilities improved, brain atrophy was reduced, and longevity was increased in animals treated with AAV vectors encoding TPP1 compared to controls (page 31; FIG 5); Worgall shows CLN2 AAV administration to the brain of children resulted in delated rate of decline compared to untreated children (page 464, 468-470), and Tardieu discloses the inclusion of the immunosuppressant regiment was based on pre-clinical studies in animals, wherein immunosuppression prevented neuroinflammation and elimination of transduced cells, and the high frequency of anti-vector neutralizing antibody production in previous intracerebral gene therapy trials in humans, consistent with antigen presentation outside the brain and a risk of the transfected cells being eliminated by the host immune cells (page 507, page 514, first column). Tardieu shows that no neutralizing antibodies were detected in the serum of the children 12 months after administration (page 514).
Thus, a skilled artisan would expect even greater improvements to the functional effects of the AAV TPP1 particles of Davidson and Worgall, when combined with immunosuppressants as taught Tardieu, Ferreira, Silva, and Gao.

Claim 15 remains rejected under 35 U.S.C. 103 as obvious over WO2012/135857 to Davidson (of record), Worgall et al. Treatment of Late Infantile Neuronal Ceroid Lipofuscinosis by CNS Administration of a Serotype 2 Adeno-Associated Virus Expressing CLN2 cDNA. Human Gene Therapy, 2008. 19:463-474, Tardieu et al. Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial. Human Gene Therapy, 2014. 25:506-516, Ferreira et al. Immune Responses to AAV-vectors, the Glybera Example from Bench to Bedside. Frontiers in Immunology, 2014. 5. Article 82, 15 pages, Silva et al. One Year Results with Extended-Release Tacrolimus/MMF, Tacrolimus/MMF and Cyclosporine/MMF in De Novo Kidney Transplant Recipients. American Journal of Transplantation, 2007. 7:595-608, and US Patent Application No. 2013/0195801 to Gao (of record), as applied to claims 1, 6-8, 10-14, 19-22, 24-28, 30-31, 36 and 38 above, and further in view of Vogler et al. Murine Mucopolysaccharidosis VII: Impact of Therapies on the Phenotype, Clinical Course, and Pathology in a Model of a Lysosomal Storage Disease. Perspectives in Pediatric Pathology, 2001. 4:421-433. Claim 15 encompasses an embodiment wherein administration of the AAV vector comprises contacting a pial cell, endothelial cell or a meningeal cell of the mammal.
The disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao combine to render obvious a method according to claim 1, wherein AAV2 vectors encoding TPP1 are administered to the brain or spinal cord, and wherein the method utilizes an immunosuppressant regimen of cyclosporine and MMF that is administered before the administration of the AAV vectors. Davidson discloses the AAV vectors are administered via the cerebrospinal fluid (CSF) (Abstract; page 13, 24, Examples).
However, none of Davidson, Worgall, Tardieu, Ferreira, Silva, or Gao disclose administration to the brain or spinal cord includes contacting a pial, endothelial or meningeal cell of the mammal, as required by instant claim 15.
Vogler discloses methods of administering gene therapy via the cerebral spinal fluid allow the vectors to contact the meninges (page 430).
Thus, it would have been obvious to the skilled artisan to combine the disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao, on methods of administering AAV vectors to the CSF to treat LSD, further with the disclosure of Vogler, wherein administration of gene therapy vectors to the CSF results in contact of the vectors with the meninges. See, MPEP 2143 I(A): (A) Combining prior art elements according to known methods to yield predictable results. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention, as contacting meningeal cells with a gene therapy vector via administration to the CSF was known at the time of the invention.

Claim 58 remains rejected under 35 U.S.C. 103 as obvious over WO2012/135857 to Davidson (of record), Worgall et al. Treatment of Late Infantile Neuronal Ceroid Lipofuscinosis by CNS Administration of a Serotype 2 Adeno-Associated Virus Expressing CLN2 cDNA. Human Gene Therapy, 2008. 19:463-474, Tardieu et al. Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial. Human Gene Therapy, 2014. 25:506-516, Ferreira et al. Immune Responses to AAV-vectors, the Glybera Example from Bench to Bedside. Frontiers in Immunology, 2014. 5. Article 82, 15 pages, Silva et al. One Year Results with Extended-Release Tacrolimus/MMF, Tacrolimus/MMF and Cyclosporine/MMF in De Novo Kidney Transplant Recipients. American Journal of Transplantation, 2007. 7:595-608, and US Patent Application No. 2013/0195801 to Gao (of record), as applied to claims 1, 6-8, 10-14, 19-22, 24-28, 30-31, 36 and 38 above, and further in view of US Patent No. 6,302,685 to Lobel (record). Claim 58 encompasses an embodiment wherein the TPP1 (CLN2) protein is encoded by SEQ ID NO:5.
The disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao are applied as in the 103 rejection above, the content of which is incorporated herein in its entirety. Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao combine to render obvious a method according to claim 1, wherein AAV vectors encoding TPP1 (CLN2) are administered to the brain or spinal cord, and wherein the method utilizes an immunosuppressant regimen of cyclosporine and MMF that is administered before the administration of the AAV vectors. Each of Davidson and Worgall discloses the AAV vectors encode TPP1 (CLN2).
However, none of Davidson, Worgall, Tardieu, Ferreira, Silva, or Gao disclose the peptide sequence encoded by TPP1.
Lobel discloses encoding CLN2 (TPP1) in viral vectors, including AAV vectors, to treat the lysosomal storage disorder late infantile neuronal ceroid lipofuscinosis (LINCL) (Abstract, column 3, lines 18-33, column 23, lines 1-33; column 25, lines 25-50). Lobel discloses that when administering a viral vector encoding CLN2 for gene therapy, the method includes co-administering an immunosuppressive agent, to avoid immune-deactivation of the virus vector (column 25, lines 51-61).
Lobel discloses TPP1 is encoded by SEQ ID NO: 3 therein, is 100% identical to instantly claimed SEQ ID NO:5.
It would have been obvious to combine the disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao on a method according to claim 1, wherein AAV vectors encoding TPP1 (CLN2) are administered to the brain or spinal cord, and wherein the method utilizes an immunosuppressant regimen of cyclosporine and MMF that is administered before the administration of the AAV vectors, further with the disclosure of Lobel, on the known amino acid sequence for TPP1. See, MPEP 2143 I(A): (A) Combining prior art elements according to known methods to yield predictable results. A skilled artisan would have had a reasonable expectation of success in practicing the claimed invention, as the claimed amino acid sequence encoded by SEQ ID NO: 5 was known, and used in a method of gene therapy at the time of the invention.

Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 6-8, 10-15, 19-22, 24-28, 30-31, 36, 38 and 58 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 10,391,184 in view of
WO2012/135857 to Davidson (of record);
Worgall et al. Treatment of Late Infantile Neuronal Ceroid Lipofuscinosis by CNS Administration of a Serotype 2 Adeno-Associated Virus Expressing CLN2 cDNA. Human Gene Therapy, 2008. 19:463-474;
Tardieu et al. Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial. Human Gene Therapy, 2014. 25:506-516;
Ferreira et al. Immune Responses to AAV-vectors, the Glybera Example from Bench to Bedside. Frontiers in Immunology, 2014. 5. Article 82, 15 pages;
Silva et al. One Year Results with Extended-Release Tacrolimus/MMF, Tacrolimus/MMF and Cyclosporine/MMF in De Novo Kidney Transplant Recipients. American Journal of Transplantation, 2007. 7:595-608; and
US Patent Application No. 2013/0195801 to Gao (of record);
Vogler et al. Murine Mucopolysaccharidosis VII: Impact of Therapies on the Phenotype, Clinical Course, and Pathology in a Model of a Lysosomal Storage Disease. Perspectives in Pediatric Pathology, 2001. 4:421-433; and
US Patent No. 6,302,685 to Lobel (record).

The disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao are applied as in the 103 rejections above.
The disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao in view of Vogler are applied as in the 103 rejections above.
The disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao in view of Lobel are applied as in the 103 rejections above.

Instant claim 1 is directed to “A method of treating a mammal having a lysosomal storage disease (LSD) associated with tripeptidylpeptidase 1 (TPP1) insufficiency, said method comprising the steps:
(a) administering to the brain or spinal cord of a mammal a plurality of adeno-associated virus (AAV) particles at a dose of about 1 x 108 to about 1 x 1015 vector genomes per kilogram (vg/kb), said AAV particles
(i) comprising an AAV2 capsid protein and a nucleic acid inserted between a pair of AAV inverted terminal repeats (ITRs), said nucleic acid encoding a polypeptide comprising TPP1 or a pro-enzyme thereof, and
(ii) being capable of transducing cells of said mammal and proteins expression of said polypeptide; and
(b) administering to said mammal a first immunosuppressive agent, wherein said first immunosuppressive agent is cyclosporine and wherein said cyclosporine is administered at a dosage of about 5-20 milligram per kilogram (mg/kg) twice a day for a period of at least 3 months, and a second immunosuppressive agent, wherein said second immunosuppressive agent is either mycophenolate or mycophenolate mofetil (MMF),
wherein said first immunosuppressive agent and said second immunosuppressive agent are administered to said mammal prior to administration of said AAV particles,
and wherein a neutralizing antibody response in said mammal is inhibited by administration of said first immunosuppressive agent and said second immunosuppressive agent,
and
wherein said mammal is a human.”
Instant claim 11 requires wherein the AAV vectors are administered to the cisterna magna, brain ventricle, etc. Instant claims 18-20 are directed to treating human populations.

Claims 1 and 2 of US Patent No 10,391,184 are directed to methods of delivering an rAAV encoding TPP1 to the brain or spinal fluid of a primate mammal, wherein the method also comprises administering an immunosuppression agent. Claim 10 requires wherein the immunosuppressant is mycophenolate.
Thus, the instant claims are an obvious variant of the claims of the earlier patent. To the extent that the instant claims require two immunosuppressants that is known from the prior art, as taught by Tardieu.
Instant claims 6-8, 10-15, 19-22, 24-28, 30-31, 36, 38 and 58 are obvious over and similar in scope to patented claims 3-20 or are obvious over the cited art, as iterated above in the 103 rejections, the content of which is incorporated herein in their entirety.

Claims 1, 6-8, 10-15, 19-22, 24-28, 30-31, 36, 38 and 58 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4-10, 12, 14-15, 19, 24-25, 31, 33-34, 37, 41, 44-49, 51 -57, 60-61, 65 and 68 of copending Application No. 16/344,298 in view of
WO2012/135857 to Davidson (of record);
Worgall et al. Treatment of Late Infantile Neuronal Ceroid Lipofuscinosis by CNS Administration of a Serotype 2 Adeno-Associated Virus Expressing CLN2 cDNA. Human Gene Therapy, 2008. 19:463-474;
Tardieu et al. Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial. Human Gene Therapy, 2014. 25:506-516;
Ferreira et al. Immune Responses to AAV-vectors, the Glybera Example from Bench to Bedside. Frontiers in Immunology, 2014. 5. Article 82, 15 pages;
Silva et al. One Year Results with Extended-Release Tacrolimus/MMF, Tacrolimus/MMF and Cyclosporine/MMF in De Novo Kidney Transplant Recipients. American Journal of Transplantation, 2007. 7:595-608;
US Patent Application No. 2013/0195801 to Gao (of record);
Vogler et al. Murine Mucopolysaccharidosis VII: Impact of Therapies on the Phenotype, Clinical Course, and Pathology in a Model of a Lysosomal Storage Disease. Perspectives in Pediatric Pathology, 2001. 4:421-433; and
US Patent No. 6,302,685 to Lobel (record).
The disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao are applied as in the 103 rejections above.
The disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao in view of Vogler are applied as in the 103 rejections above.
The disclosures of Davidson, Worgall, Tardieu, Ferreira, Silva, and Gao in view of Lobel are applied as in the 103 rejections above.

Instant claim 1 is presented above.
Claims 1, 4-10, 12, 14-15, 19, 24-25, 31, 33-34, 37, 41, 44-49, 51 -57, 60-61, 65 and 68 of the ‘298 Application are directed to methods of administering AAV particles to the brain of a mammal, wherein the AAV encodes a lysosomal hydrolase, including TPP1, and wherein the mammal treated is a human. Claims 1, 31, and 33-34 requires administering one or more immunosuppressants wherein the immunosuppressants are cyclosporine, prior to administering the AAV. Claim 41 requires wherein the AAV particles are administered in a dose of 1 x108 to 1 x 1015 vg/kg. Claim 47 requires wherein the mammal is a human.
The claims of the ‘298 application do not require wherein the second immunosuppressant is MMF, or wherein said cyclosporine is administered at a dosage of about 5-20 milligram per kilogram (mg/kg) twice a day for a period of at least 3 months as required in the instant claims.
However, the administration of cyclosporine and MMF, wherein the cyclosporine is administered in the claimed regimen is obvious from the teachings of Tardieu, Ferreira and Silva, as iterated above.
Instant claims 6-8, 10-15, 19-22, 24-28, 30-31, 36, 38 and 58 are obvious over and similar in scope to application ‘298 claims 4-10, 12, 14-15, 19, 25, 37, 44-46, 48-49, 51 -57, 60-61, 65 and 68 or are obvious over the cited art, as iterated above in the 103 rejections, the content of which is incorporated herein in their entirety.
This is a provisional nonstatutory double patenting rejection.

RESPONSE TO ARGUMENTS
Applicant requests that the double patenting rejections be withdrawn for the same reasons provided against the 35 U.S.C. 103 rejection. This request is denied because the arguments are not convincing of error as to the obviousness rejection for the reasons set forth above.

Conclusion
No claims are allowed. No claims are free of the prior art.

FINAL REJECTION
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.

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/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633