Patent Application 17771627 - COMPOSITIONS AND METHODS FOR TREATING GLYCOGEN

Title: COMPOSITIONS AND METHODS FOR TREATING GLYCOGEN STORAGE DISORDERS

Application Information

Invention Title: COMPOSITIONS AND METHODS FOR TREATING GLYCOGEN STORAGE DISORDERS
Application Number: 17771627
Submission Date: 2025-04-09T00:00:00.000Z
Effective Filing Date: 2022-04-25T00:00:00.000Z
Filing Date: 2022-04-25T00:00:00.000Z
National Class: 424
National Sub-Class: 093200
Examiner Employee Number: 81194
Art Unit: 1632
Tech Center: 1600

Rejection Summary

102 Rejections: 2
103 Rejections: 3

Cited Patents

No patents were cited in this rejection.

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 .

Preliminary amendments to the claims dated 2/22/2023 are acknowledged. New claims 253-272 are under consideration in this office action.

Drawings
The drawings are objected to under 37 CFR 1.83(a) because they fail to show color/grey scale distinction between the controls points and the treatment points on the graphs for Figures 9A, 9B, and 10A as described in the specification. Any structural detail that is essential for a proper understanding of the disclosed invention should be shown in the drawing. MPEP § 608.02(d). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.

Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.

The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.

(1) Claims 268-269 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
When determining if a recited genus has adequate written description:
(1) the broadest reasonable interpretation of the genus is determined;
(2) the disclosure is examined to determine if the specification has provided a representative number of species to describe the complete structure of the genus;
(3) the disclosure is examined to determine whether a representative number of species have been sufficiently described by other relevant characteristics, specified features and functional attributes that would distinguish different members of the claimed genus; and
(4) the state of the art is examined to the determine if it supports/supplement the genus description in the specification in a manner that would demonstrate the application was in possession of the claimed genus at the time of effectively filing.

Broadest Reasonable Interpretation (BRI)
(i) Claim 268 recites the genus “the MCK promoter has a nucleic acid sequence that is at least 85% identical to SEQ ID NO:1”.
(ii) Claim 269 recites the genus, “the GAA has an amino acid sequence that is at least 85% identical to SEQ ID NO:2”.
The specification provides a definition for percent sequence identity stating (citation from pre-grant publication):
[0160] “Percent (%) sequence identity” with respect to a reference polynucleotide or polypeptide sequence is defined as the percentage of nucleic acids or amino acids in a candidate sequence that are identical to the nucleic acids or amino acids in the reference polynucleotide or polypeptide sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity.
(i) the genus encompasses a nucleic acid sequences that are a fragments of SEQ ID NO:1 or a variants having substitution, deletions, and/or additions that result in a nucleic acid sequence having no less than 85% identity to 100% identity to SEQ ID NO:1. This genus of sequence encompasses homologues, orthologues, codon optimized sequences and structurally similar sequences with different functions or no function, among others. Thus the BRI for the genus “at least 85% identical to SEQ ID NO:1 is quite broad with a vastly large number of diverse sequences structurally and functionally.
(ii) the genus of sequences encompasses an amino acid sequence that is a fragment of SEQ ID NO:2 or a variant having substitution, deletions, and/or additions that results in a amino acid sequence having no less than 85% identity to 100% identity to SEQ ID NO:2. While the claim recites an amino acid sequence with at least 85% identity to SEQ ID NO:2, the base claims recites that the GAA is encoded by an transgene (i.e. a nucleic acid sequence). As such, the sequence under consideration in genus is a nucleic acid encoding said fragments or variants of SEQ ID NO:2. The sequence therefore can have combinations of different nucleic acid codon that encode the same amino acid sequence of SEQ ID NO:2, fragments thereof, or variants thereof. The sequences can be further codon optimized or changed in any way as long as at least 85% of the sequence structure is maintained, regardless of functional attributes. Thus the BRI for the genus “at least 85% identical to SEQ ID NO:1 is quite broad with a vastly large number of diverse structurally and functionally.

Specification Description
(i) MCK promoter of SEQ ID NO:1
The specification describes the following (citations from pre-grant publication):
[0041] In some embodiments, the promoter is a MCK promoter. The MCK promoter may have, for example, a nucleic acid sequence that is at least 85% identical to SEQ ID NO: 1 (e.g., a nucleic acid sequence that is 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 1). In some embodiments, the MCK promoter has a nucleic acid sequence that is at least 90% identical to SEQ ID NO: 1 (e.g., a nucleic acid sequence that is 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 1). In some embodiments, the MCK promoter has a nucleic acid sequence that is at least 95% identical to SEQ ID NO: 1 (e.g., a nucleic acid sequence that is 95%, 96%, 97%, 98%, 99%, or 100% identical to SEQ ID NO: 1). In some embodiments, the MCK promoter has a nucleic acid sequence that is at least 97% identical to SEQ ID NO: 1 (e.g., a nucleic acid sequence that is 97%, 98%, 99%, or 100% identical to SEQ ID NO: 1). In some embodiments, the MCK promoter has a nucleic acid sequence that is at least 98% identical to SEQ ID NO: 1 (e.g., a nucleic acid sequence that is 98%, 99%, or 100% identical to SEQ ID NO: 1). In some embodiments, the MCK promoter has a nucleic acid sequence that is at least 99% identical to SEQ ID NO: 1 (e.g., a nucleic acid sequence that is 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or 100% identical to SEQ ID NO: 1). In some embodiments, the MCK promoter has a nucleic acid sequence that is 100% identical to SEQ ID NO: 1.
(ii) GAA of SEQ ID NO:2
The specification describes the following (citations from pre-grant publication):
[0172] As used herein in the context of a therapeutic protein, such as GAA, the use of the protein name refers to the gene encoding the protein or the corresponding protein product, depending upon the context, as will be appreciated by one of skill in the art. The term “GAA” includes wild-type forms of the GAA gene or protein, as well as variants (e.g., splice variants, truncations, concatemers, and fusion constructs, among others) of wild-type GAA proteins that retain therapeutic activity of the wild-type GAA protein, as well as nucleic acids encoding the same. Examples of such variants are proteins having at least 70% sequence identity (e.g., 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 99.9% identity, or more) to an amino acid sequence of a wild-type GAA protein, such as SEQ ID NO: 2, below. And Table 2.
[0173] Similarly, as used herein in the context of a transcription regulatory element, the term “MCK promoter” refers to a wild-type MCK promoter, such as a wild-type human or murine MCK promoter, as well as variants (e.g., variants containing insertions, deletions, and/or substitutions of one or more nucleic acid residues) to the extent that the promoter retains the ability to induce expression of an operably linked gene in a muscle and/or neuronal cell. An exemplary MCK promoter that may be used in conjunction with the compositions and methods of the disclosure is shown in SEQ ID NO: 1, below and Table 3.
[0181] Exemplary genes encoding a GAA polypeptide that may be used in conjunction with the compositions and methods described herein include genes encoding the wild-type GAA protein set forth in SEQ ID NO: 2, as well as functional GAA enzymes that are at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical) to the amino acid sequence of SEQ ID NO: 2. Genes encoding a GAA polypeptide that may be used in conjunction with the compositions and methods described herein further include those that have one or more amino acid substitutions, such as those that have one or more conservative amino acid substitutions, with respect to the amino acid sequence set forth in SEQ ID NO: 2. For instance, GAA polypeptides that may be used in conjunction with the compositions and methods described herein include those that have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, or more, conservative amino acid substitutions with respect to the amino acid sequence of SEQ ID NO: 2.
[0182] For example, in some embodiments of the disclosure, the gene encoding a GAA polypeptide has a nucleic acid sequence that is at least 85% identical (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9%, or 100% identical) to the nucleic acid sequence of SEQ ID NO: 3. The nucleic acid sequence of SEQ ID NO: 3 encodes the GAA polypeptide having the amino acid sequence of SEQ ID NO: 2, above. The nucleic acid sequence of SEQ ID NO: 3 is as follows and Table 5.
Thus while the specification generically contemplates (i) a sequence with at least 85% sequence identity to SEQ ID NO:1 and (ii) an amino acid sequence with at least 85% sequence identity to SEQ ID NO:2, the specification solely provides species examples for the full length wild type human sequences of SEQ ID NOS:1-3, with SEQ ID NO:3 being the nucleic acid sequence encoding wild-type GAA. The specification provides no description for further relevant domains or structures that need to be conserved in SEQ ID NOS:1-3. The specification provides no description of sequence elements or point mutations that can be altered to arrive at the fragment and variant sequence encompass by the BRI. As such, the specification only provide description of wild-type species with 100% identity to SEQ ID NOS:1 and 2 and fails to describe any of the other structures that would give rise to fragments and variants as the breadth of the claimed genus encompasses. As such the specification fails to describe a representative number of species by other relevant characteristics, specified features and functional attributes that would distinguish different members of the claimed genus or describe the complete structure of the genus of “at least 85% identical to SEQ ID NO” 1 and 2.
State of the Art
(i) MCK promoter of SEQ ID NO:1
Chamberlain (US 6,869,777 pub date: 2005) describes a MCK promoter of SEQ ID NO:61 with 85.7% identity to SEQ ID NO:1 of the instant application. Xiao (US 7,001,761 pub date: 2006) discloses a MCK promoter of SEQ ID NO:31 with 97.9% identity. Martin (US 10,980,897 pub date:2022 but available in correspond WO document in 2017) describes SEQ ID NO:2 with 90% identity to SEQ ID NO:1. Lochmuller (US 11,338,045 pub date:2022 but available in corresponding WO document in 2019) discloses SEQ ID NO 4 with 88% sequence identity to SEQ ID NO:1. While the prior art does describe a few variant species examples of SEQ ID NO:1 of the instant application, a greater number of other species are encompassed by the BRI of the instant claims. None of the above prior art descriptions provide particular discussions of fragments or variants that can be made to the wild-type MCK promoter other than the variant that they disclose above. As such, one of ordinary skill in the art before the time of effective filing could not envision the types of variants and fragments that would provide the complete structure of the genus “at least 85% identical to SEQ ID NO:1”.
(ii) GAA of SEQ ID NO:2
Clark et al (Science 302:1960-1963, 12/12/2003) describes a mouse sequence with 77.1% similarity to SEQ ID NO:2 and a chimp sequence with 67.8% sequence similarity to SEQ ID NO:2 (see Alignment of Clark et al reference sequences with SEQ ID NO:2 printed 2025 pages 1-22). This is the closest prior art found to SEQ ID NO:2. Clark et al. describes, “Even though human and chimpanzee gene sequences are nearly 99% identical, sequence comparisons can nevertheless be highly informative in identifying biologically important changes that have occurred since our ancestral lineages diverged. We analyzed alignments of 7645 chimpanzee gene sequences to their human and mouse orthologs. These three-species sequence alignments allowed us to identify genes undergoing natural selection along the human and chimp lineage by fitting models that include parameters specifying rates of synonymous and nonsynonymous nucleotide substitution.” See abstract. “To identify genes and biological processes that have been most altered by our recent evolutionary divergence from other primates, we need to fit the data to models of sequence divergence that allow us to distinguish between divergence caused by random drift and divergence driven by natural selection. Early observations of unexpectedly low levels of protein divergence between humans and chimpanzees led to the hypothesis that most of the evolutionary changes must have occurred at the level of gene regulation…. Recently, much more extensive efforts at DNA sequencing in nonhuman primates has confirmed the very close evolutionary relationship between humans and chimps…, with an average nucleotide divergence of just 1.2%.... The role of protein divergence in causing morphological, physiological, and behavioral differences between these two species, however, remains unknown. See page 1960 paragraph bridging cols 1-3.
Regarding Pompe disease (aka acid α-Glucosidase Deficiency ‘GSDII’ or acid maltase deficiency), a deficiency in GAA results in glycogen accumulation in lysosomes and particularly negatively impacts skeletal muscle and heart function. There is a spectrum of the disease in humans ranging from infantile-onset hypotonia and lethal cardiomyopathy to adult-onset progressive weakness that leads to respiratory failure. There are no naturally occurring animal models for GAA deficiency and Pompe disease (Acid α-glucosidase-an overview. ScienceDirect Topics. sciencedirect.com/science/article/pii/B978012385157400083X. pages 1-11, printed 2025. See page 8 of 11). On the molecular genetics level, Traverna et al (Aging 12(15):15856-15874, 2020) reports, “The mutational spectrum of GAA is very heterogeneous, genetic variants are often “private”, found only in a single family or in a small population…. These variants can be: (I) point mutations, which can affect the protein functionality and stability or the splicing process, (II) small and large deletions and insertions. They cause the transcription of unstable mRNAs with consequences on: protein synthesis, post-translational modifications, lysosomal trafficking and in proteolytic nature of GAA. The most commonly reported missense mutations in PD occur in unexposed amino acid residues, causing structural misfolding, therefore PD can be considered a protein folding dysfunction... In 2002, it has been reported that GAA variants were clustered in three critical regions of gene: exon 2, which contains the start codon; exon 10 and 11, which encode the catalytic site; and exon 14, which encodes for a highly conserved region of GAA protein…. However, several papers reported mutations in the whole gene Pompe disease GAA variant database…, last update in June 2019, reports 562 GAA variants, among these, 422 are disease-associated and 140 are considered Genetic Variants of Unknown Significance (GVUS).” See p.15857, ‘Molecular genetics of PD’ section.
As such, the art before the time of filing does not supplement the lack of description of sequences with at least 85% identity to SEQ ID NO:2. Further, prior art alignment and Clark et al teach that there is sequence divergence between different orthologues and even individuals and the role of such protein divergence in causing morphological, physiological, and behavioral differences between these two species remains unknown. In the case of Pompe disease, this divergence in GAA sequence between species is consistent with the finding that there are no natural animal models of Pompe disease, and it is unique to the genetics of human GAA gene structure. Even further, Traverna et al. demonstrates within human, Pompe disease is a heterogenous disease associated with a plethora of genetic mutations in the GAA gene sequence that appear to be unique to individuals. As such, from the prior art, one of ordinary skill would not be able to predictably envision what types of sequence variants and fragments of SEQ ID NO:2 would be encompassed by at least 85% identity to SEQ ID NO:2 to supplement the shortcomings of the descriptions provided by the instant application.
In conclusion, the genus (i), “the MCK promoter has a nucleic acid sequence that is at least 85% identical to SEQ ID NO:1”, and the genus (ii) “the GAA has an amino acid sequence that is at least 85% identical to SEQ ID NO:2” lack adequate written description because the disclosure of the application fails to described a representative number of species of (i) and (ii) to adequately describe the complete structure of (i) and (ii). The specification also fails to adequately describe a representative number of species have been sufficiently described by other relevant characteristics, specified features and functional attributes that would distinguish different members of (i) and (ii). The prior art fails to provide sufficient description of (i) and (ii) to supplement the shortcomings of the application disclosure and further describes that the art of the instant invention is unpredictable. As such, one of ordinary skill could not envision the full breadth of genus (i) and (ii) in a manner that would lead them to believe the application was in possession of the full breadth of (i) and (ii) at before the time of effectively filing.

(2) Claims 253-271 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for
Regarding claims 253-269, A method of clearing glycogen storage and improving cardiac, respiratory, and muscle function in a subject with Pompe disease comprising: administering to the subject an AAV2/8 vector comprising a transgene encoding GAA operably linked to MCK promoter, wherein the AAV vector is administered in an amount between 1x1013 vg/kg to 3 x1014 vg/kg and is administered (i) directly to muscle or heart or (ii) intravenously, and wherein said administering results in increased expression of GAA.
Regarding claims 270-271, these claims are enabled for the limitations above or an ERT therapy that administers rhGAA to said subject.
The specification does not reasonably provide enablement for:
1) treating or curing any and all symptoms of Pompe disease;
2) any AAV vector;
3) any route of administration; and
4) for claims 270-271, an agent that increases GAA expression.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considers whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would require undue experimentation to make and use the claimed invention and whether working examples have been provided. When determining whether a specification meets the enablement requirements, some of the factors that need to be analyzed are: the breadth of the claims, the nature of the invention, the state of the prior art, the level of one of ordinary skill, the level of predictability in the art, the amount of direction provided by the inventor, the existence of working examples, and whether the quantity of any necessary experimentation to make and use the invention based on the content of the disclosure is “undue”.
Nature of Invention: Gene therapy for treating Pompe disease by administering an AAV vector encoding GAA.
Breadth of the Claims: The claims broadly recite, “a method of treating Pompe disease” without particular recitation of symptoms. As such the broadest reasonable interpretation (BRI) is any symptoms directly/primarily or indirect/secondarily caused by Pompe disease (i.e. a deficiency in GAA enzyme expression and/or activity). The claims also recite “administering” an AAV vector without any recitation of a route of administration. As such the BRI is any administration including systemically, intravenously, intrapulmonary, intramuscularly, intracranially, intrathecally, subdermal, subcutaneously, intraocular, intrarenal, peritoneal, topically, orally, among many other routes of administration. The claims do not specify any promoter used in the transgene. As such, the BRI of the promoter is any promoter capable of directing expression in any tissue. Regarding claims 270-271, the BRI of the claimed agent is any agent (protein, nucleic acid, DNA, RNA, iRNA, small molecule, conditional stimulation (electrical, mechanical, environments, etc…) among others. The agent can be one that directly impacts GAA (such as one that results in exogenous GAA protein or GAA gene expression) or indirectly (a factor that modulates upstream or downstream of GAA).
Specification Guidance:
Much of the specification’s disclosure describes different AAV viral dosage administration schedules. The specification describes the following (citations from pre-grant publication):
[0175] The present disclosure is based, in part, on the discovery of that particular doses of AAV vectors containing a GAA transgene are capable of achieving a therapeutic increase in GAA expression and activity in patients suffering from Pompe disease while suppressing toxic side effects. Particularly, doses of AAV vectors containing a transgene encoding GAA ranging from about 1×10.sup.13 vg/kg to about 3×10.sup.14 vg/kg (e.g., from about 3×10.sup.13 vg/kg to about 2×10.sup.14 vg/kg, such as a dose of about 4×10.sup.13 vg/kg, 5×10.sup.13 vg/kg, 6×10.sup.13 vg/kg, 7×10.sup.13 vg/kg, 8×10.sup.13 vg/kg, 9×10.sup.13 vg/kg, or 1×10.sup.14 vg/kg) can engender a beneficial increase in GAA expression and activity in a patient having Pompe disease while avoiding toxic side effects that can be associated with overexpression of GAA or administration of excessive quantities of viral vector. Using the compositions and methods of the disclosure, an AAV vector may be administered to the patient in an amount that is sufficient to enhance the patient's expression of GAA and reduce cellular accumulation of glycogen in the patient's neuronal and muscle tissue, without inducing toxic side effects.
[0178] Pompe disease (also known as glycogen storage disease type II, or GSD II) is caused by deficiency of the lysosomal enzyme GAA. The disease is an inborn error of metabolism in which a GAA deficiency ultimately results in glycogen accumulation in all tissues, especially striated muscle cells. In addition, the effect of glycogen accumulation within the central nervous system and its effect on skeletal muscle function have been documented.
[0179] Three clinical forms of this disorder are known: infantile, juvenile, and adult. Infantile Pompe disease has its onset shortly after birth and presents with progressive muscular weakness and cardiac failure. Infantile forms of Pompe are also characterized by a rapid development of cardiomyopathy, and patients often display myopathy and neuropathy leading to death typically in the first year of life. Symptoms in adult and juvenile patients occur later in life, and skeletal muscles and neurons are primarily involved. Patients exhibiting this form of Pompe disease eventually die due to respiratory insufficiency. Patients may exceptionally survive for more than six decades. There is a correlation between the severity of the disease and the residual acid α-glucosidase activity, the activity being 10-20% of normal in late onset and less than 2% in early onset forms of the disease.
[0184]-[0209] describe Dosing Regimens Involving AAV-GAA Vectors.
[0225] Viral vectors, such as AAV vectors and others described herein, containing the transcription regulatory element operably linked to a therapeutic transgene may be administered to a patient (e.g., a human patient) by a variety of routes of administration. The route of administration may vary, for example, with the onset and severity of disease, and may include, e.g., intradermal, transdermal, parenteral, intravenous, intramuscular, intranasal, subcutaneous, percutaneous, intratracheal, intraperitoneal, intraarterial, intravascular, inhalation, perfusion, lavage, and oral administration. Intravascular administration includes delivery into the vasculature of a patient. In some embodiments, the administration is into a vessel considered to be a vein (intravenous), and in some administration, the administration is into a vessel considered to be an artery (intraarterial). Veins include, but are not limited to, the internal jugular vein, a peripheral vein, a coronary vein, a hepatic vein, the portal vein, great saphenous vein, the pulmonary vein, superior vena cava, inferior vena cava, a gastric vein, a splenic vein, inferior mesenteric vein, superior mesenteric vein, cephalic vein, and/or femoral vein. Arteries include, but are not limited to, coronary artery, pulmonary artery, brachial artery, internal carotid artery, aortic arch, femoral artery, peripheral artery, and/or ciliary artery. It is contemplated that delivery may be through or to an arteriole or capillary.
Thus, the specification generically describes treating symptoms known in the art for Pompe disease and administering the vector by any route of administration known in the art. The vast majority of the specific guidance in the specification is to dosage and administration schedule with the described purpose of treating Pompe without eliciting harmful side effects of eliciting an immune response to the exogenous AAV vector and its payload and the exogenous transgene product.
Working Examples:
Example 1. Establishing Therapeutic Expression of Acid Alpha-Glucosidase in Mouse Models of Pompe Disease while Avoiding Toxic Side Effects.
[0230] The objective of this study was to evaluate the pharmacodynamic response together with potential toxicity of an AAV2/8 vector containing a GAA transgene operably linked to a muscle creatine kinase (MCK) promoter (referred to herein as “AAV2/8-MCK-GAA”) in adult Gaa.sup.−/− mice for a period of 12 weeks post dosing.
[0231] Seventy-two Gaa−/− mice and 18 wild type littermates were enrolled on study. Eighteen mice (9 each male and female; 10-12 weeks old) per group were administered either a single IV injection (via tail vein) of vehicle or AAV2/8-MCK-GAA (rAAV8-eMCK-hGAA) at doses of 0.3×10.sup.14, 1.0×10.sup.14, or 3.0×10.sup.14 vg/kg. Of these, Cohort-1 animals (5 males and 5 females per dose group plus vehicle controls) were designated for safety evaluation.
[0244] Analysis of diaphragm, heart, and quadricep biopsies revealed a dose-dependent decrease in glycogen concentration in AAV2/8-MCK-GAA-treated mice. Independently of which tissue was tested, the overall pattern of results across muscles was the same.
[0251] A positive effect of AAV2/8-MCK-GAA treatment was observed on glycogen clearance across all tested dosage groups and in all examined tissues. The greatest improvement was observed in the mid and high dose treatment groups, with glycogen normalized to the level observed in WT controls.
Example 2. Establishing Therapeutic Expression of Acid Alpha-Glucosidase in Mouse Models of Pompe Disease while Avoiding Toxic Side Effects
[0253] The objective of this GLP study was to examine the potential toxicity and safety pharmacology of AAV2/8-MCK-GAA in juvenile cynomolgus monkeys for a period of 12 weeks post-dosing.
[0254] Twenty-five juvenile monkeys 2-4 years old (14 males, 11 females) with low serum anti-AAV8 neutralizing antibody levels (titer of 5 or less for AAV2/8-MCK-GAA treated) were enrolled on study. Table 3 outlines the study design. Animals were administered a single IV infusion of vehicle, one of three doses (0.6×10.sup.14, 2×10.sup.14, or 5×10.sup.14 vg/kg) of AAV2/8-MCK-humanGAA (AAV2/8-MCK-GAA), or one dose (2×10.sup.14 vg/kg) of AAV2/8-MCK-cynomolgus GAA on study Day 1.
[0306] Administration of AAV2/8-MCK-GAA by intravenous infusion was tolerated up to 0.6×10.sup.14 vg/kg, but at the highest dose of 5×10.sup.14 vg/kg resulted in the unscheduled euthanasia of two animals, one female (animal 4501) on Day 79 and one male (animal 4003) on Day 82. Furthermore, in AAV2/8-MCK-cynomolgusGAA-treated animals, cynomolgus GAA-protein levels also increased in all tissues examined. Neither T-cell mediated anti-AAV8/GAA nor total anti-GAA antibodies appeared to negatively affect GAA protein or tissue enzyme activity levels.
[0308] In summary, the low dose (0.6×10.sup.14 vg/kg) of AAV2/8-MCK-GAA was well tolerated, whereas doses ≥2×10.sup.14 vg/kg were consistent with myocardial injury and accompanying mixed cell inflammation in muscles with occasional myofiber degeneration but also liver, adipose tissue, and dorsal root ganglia. An AAV2/8-MCK-GAA dose of 0.6×10.sup.14 vg/kg was defined as the no adverse effect limit (NOAEL).
No therapeutic or treatment of symptoms of Pompe were described in Example 2.
Example 3. Treatment of Pompe Disease in Human Patients by Administration of AAV-GAA Vectors in Accordance with a Dosing Regimen of the Disclosure. This example is a prophetic example describing how a human patient will be administered an AAV-GAA vector.
Thus, the working examples provides specific guidance to the use of one specific AAV vector comprising a transgene encoding GAA operably linked to a muscle specific MKC promoter that is administered at different doses (low, medium, and high) intravenously to a mouse model of Pompe disease or a monkey without Pompe disease both in a single dose. The examples narrowly describe that mouse model demonstrated improved glycogen storage clearance from the muscle and heart. The monkey experiment demonstrated a dosage limit for tolerance of the AAV vector that allowed for increased GAA expression in muscle and heart that did not result in anti-AAV and anti-GAA expression at a level that altered GAA protein increase.
However, the specification fails to provide broader specific guidance to any other route of administration, any other vectors that have promoters that express in tissue other than muscle, any other AAV vector than AAV2/8 and treatment any and all symptoms of Pompe disease. As such, the specification does not enable these broader embodiments.
Regarding claims 270-271, while the specification recites these claims, the specification does not provide specific guidance to any other agent than AAV-GAA gene therapy vectors. As such, the specification and working examples of the disclosure fails to provide enabling guidance to any other “agent” as claimed.
State of the Art:
Traverna et al (Aging 12(15):15856-15874, 2020) reports, “ERT [GAA protein therapy] improves the cardiac and respiratory functions and contributes to extend the lifespan of IOPD patients. However, it is frequently associated with the development of neutralizing humoral immune responses against rhGAA that decreases treatment efficacy and survival…. The limitations of therapy have encouraged efforts to enhance the efficacy of the current therapy and to develop new approaches including gene therapy… The results showed an efficient clearance of glycogen storage in muscle and the improvement of the muscle and the cardiac and respiratory functions. One limitation of the systemic route to target muscles is the use of high doses of vector…. Moreover, muscle specific expression of GAA can increase the risk to develop anti-GAA antibodies causing a possible immunotoxicity. Another strategy to develop gene therapy for PD consists in the stable expression of GAA in liver. It was demonstrated that adenoviral GAA transfer mediates the crosscorrection in skeletal muscles. The major limitation of this approach for PD is that hepatic gene transfer does not persist at long term.” See page 15865. Also see Ronzitti et al (Ann Transl Med 2019;7(13):287 dx.doi.org/10.21037/atm.pp 1-15).
Regarding claims 270-271, ERT is the only other therapy described around the time of filing that has some but limited ability to treat some symptoms of Pompe disease. However, as discussed above, the prior art teaches a great deal of unpredictability in ERT, GAA gene therapy, and overall treatment of Pompe disease. As such, the art does not provide adequate specific guidance to “an agent that increases GAA expression” other then ERT and GAA gene therapy to some degree. Thus, the art does not provide enabling guidance to the breadth of the claimed agent to supplement the shortcomings of the specification.
Thus the state of the art before the time of filing and post-filing describes a high degree of unpredictability in both ERT and GAA gene therapy approaches. While the specification does not provide some guidance to administrations schedules that may mediate some of the unpredictabilites AAV vector and GAA elicited immune responses, it fails to provide specific guidance to overcome issue of using any route of administration, any vector, expression of the GAA in any tissue, and treating any symptom of Pompe disease as the claims embrace. Furthermore, the specification appears to overcome some of the issues of immune response to the AAV vector and GAA via the use of one specific vector that has muscles specific expression and it delivered in one specific way at a specific concentration. As such, these element appears to be required for the improvement. Thus, the breadth of the claims lack enablement because the specification solely provides specific guidance to a much narrow gene therapy approach using one specific AAV vector encoding GAA operably liked to a MCK promoter administered intravenously that improves glycogen storage clearance and is expressed in a manner that increases GAA without interference with anti-AAV and anti-GAA immune response. Given the great degree of unpredictability in this art, a great deal of discovery experimentation would be required post-filing to determine its potential as a means of treat Pompe disease as broadly claimed. This level of post-filing experiment would be considered beyond routine optimization and thus would be undue.

Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –

(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.

(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.

(1) Claim(s) 253-256, 264-267, and 270-272 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Byrne (WO 2013/192317 A2 pub date 12/27/2013 effectively filed 6/19/2012; of record in IDS 2/22/2023).
Regarding claim 253, Bryne discloses administering an AAV virion to a subject having GAA deficiency (i.e. Pompe disease), resulting in respiratory deficit and improving phrenic nerve activity (p. 10, last paragraph to p. 11, line 7). Expected dosage for IV administration will be in the range of 1012-1015 . For example for a 70 kg human, a 1 to 10 ml injection (i.e. single dose) of 1012-1015 particles is an appropriate does (p. 25, lines 10-15).
Regarding claims 254-255, the above dosage range comprises the dosage of the claimed ranges.
Regarding claim 256, a single 1 to 10 ml injection as discussed above discloses a single dose as claimed.
Regarding claim 264, an i.v. injection is disclosed as discussed above.
Regarding claim 265, Bryan discloses the AAV can be an rAAV2 vector encoding GAA pseudotyped with a capsid gene derived from AAV of a different serotype (e.g., AAV1, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9), an example AAV2/9 (p. 22, lines 15-25). These disclosure encompass both AAV2/8 and AAV2/9.
Regarding claim 266-267, Bryan discloses a MKC promoter (p. 17, lines 18-22).
Regarding claim 270-271, the breadth of these claims encompass the method that is the same as the method disclosed in claim 253 of the instant application. As such, the disclosure discussed above by Bryan encompass the limitations of claims 270-271.
Regarding claim 272, Bryan discloses the vector as discussed above and describes a method of administering it to a human patient as discussed above. As such, Bryan discloses the limitations of the claimed kit.
(2) Claim(s) 270-271 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kishnani (Kishnani et al. NEUROLOGY 2007;68:99–109).
Regarding claim 270, Kishnani discloses patients, diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy, received IV infusions of rhGAA at 20 mg/kg (n 9) or 40 mg/kg (n 9) every other week. Recombinant human acid α-glucosidase is an effective for treatment of infantile-onset Pompe disease (see abstract).
Regarding claim 271, Kishnani teaches that the agent is a rhGAA protein.
In conclusion, Kishnani anticipates the claims.

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.

(1) Claim(s) 268 is/are rejected under 35 U.S.C. 103 as being unpatentable over Byrne (WO 2013/192317 A2 pub date 12/27/2013 effectively filed 6/19/2012; of record in IDS 2/22/2023) as applied to claims 253-256, 264-267, and 270-272 above, and further in view of Xiao (US 7,001,761 pub date:2/16/2006).
Regarding claim 268, Bryne teaches the claim limitations as discussed above. Bryne does not teach that the MCK promoter is specifically a species having at least 85% identical to SEQ ID NO:1.
However, at the time of the invention, Xiao teaches multiple AAV vectors comprising mini-dystrophin genes operable linked to a MCK promoter (SEQ ID NOS:26-32). The promoters of SEQ ID NOS:26-30 and 32, taught by Xiao are 100% identical to SEQ ID NO:1 of the instant application. The promoter of SEQ ID NO:31, taught by Xiao, is 97.9% identical to SEQ ID NO:1 of the instant application (col 13, lines 1-31). Further Xiao teaches that the MCK promoter of these AAV vectors successfully induced muscle specific expression of the mini-gene which lead to the therapeutic result of improve muscle contractile force (col 17; lines 22-27). Thus Xiao at least demonstrates that the MCK promoters taught by Xiao are a predictable equivalent to the MCK promoter of SEQ ID NO:1 in the instant application. Further, one would be motivated to use the promoters of SEQ ID NOS:26-32 taught by Xiao because Xiao teaches that the promoter drives muscle specific expression of a transgene at therapeutic levels.
As such, it would have been obvious to an artisan of ordinary skill before the time of effectively filing, to simply substitute the MCK promoter of SEQ ID NOS:26-32, taught by Xiao, in place of the MCK promoter used in Bryne to predictably arrive at the AAV vector and method of claim 268. One would have a reasonable expectation of success with the substitution because the methods of such a substitution were well known in the art and because Xiao provide multiple examples of successfully using the MCK promoter in AAV vectors for muscle specific expression. Further, one would be motivated to use the MCK promoter of Xiao in the method of Bryne because Xiao demonstrates that it is a strong promoter for muscle-specific expression at therapeutic levels. Thus, Bryne in view of Xiao renders claim 268 obvious.

(2) Claim(s) 269 is/are rejected under 35 U.S.C. 103 as being unpatentable over Byrne (WO 2013/192317 A2 pub date 12/27/2013 effectively filed 6/19/2012; of record in IDS 2/22/2023) as applied to claims 253-256, 264-267, and 270-272 above, and further in view of Medin (US 11,597,917 effectively filed 6/6/2017).
Regarding claim 269, Bryne teaches the claim limitations as discussed above. Bryne does not teach that the GAA has an amino acid sequence that is at least 85% identical to SEQ ID NO:2.
However, Medin teaches a viral vector comprising a gene encoding a GAA amino acid sequence set forth in SEQ ID NO:9. SEQ ID NO:9 is an mRNA sequence encoding an amino acid sequence with 100% identity to SEQ ID NO:2 of the instant claim. This viral vector is intended for treatment of Pompe disease (col 10, last paragraph to col 11, line 8).
As such, it would have been obvious to an artisan of ordinary skill before the time of effectively filing to simply substitute the GAA transgene sequence of Bryne with SEQ ID NO:9, taught by Medin to predictably arrive at the method of claim 269. One would have a reasonable expectation of success because molecular biology methods for making the substitution were long established and predicable in the prior art and Medin teaches that SEQ ID NO:9 can be used in viral vectors and can be use to treat Pompe disease and therefore is a predicable equivalent sequence serving the same purpose as taught by Bryne. As such, Bryne in view of Medin render claim 269 obvious.

(3) Claim(s) 258-263 is/are rejected under 35 U.S.C. 103 as being unpatentable over Byrne (WO 2013/192317 A2 pub date 12/27/2013 effectively filed 6/19/2012; of record in IDS 2/22/2023).
Regarding claims 258-263, Bryne teaches the limitations of the claimed method including the viral dosage as taught above. Bryne is silent on the delivery of a dose 2 or more times, the total dosage over multiple AAV administrations, and the timing of delivery of multiple dosages as recited in these claims.
However, Bryne teaches that toxicity and therapeutic efficacy of AAV administration in the methods of their invention can be determined by standard pharmaceutical procedures. Further Bryne teaches as is well known in the medical and veterinary arts, dosage for any one animal depends on many factors, including subject’s size, body surface area, age the particular composition administered, time, route of administration, general health, and other drugs administered concurrently (p. 25, lines 1-15). As such, Bryne teaches that determining the amount, number of dosages, and timing of dosages is routine in the prior art. Therefore, it would have been obvious to an artisan of ordinary skill before the time of effectively filing to determine the optimal dosage, number of administrations, and timing of the number of administration using well established pharmacological methods to predictably arrive at the limitations of the claims.
Further, However, MPEP § 2144.05 (II) states the following:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In reHoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc.v.Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In reKulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree “will not sustain a patent”); In re Williams, 36 F.2d 436, 438 (CCPA 1929) (“It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.”). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
Dosage administration schedule is ultimately a determination of concentration ranges A review of the specification in the instant application fails to provide evidence that the claimed dosage administration schedule are critical. Absent such evidence it would have been obvious to an artisan of ordinary skill at the time of effectively filing Smith to try a finite number of possible concentration of the AAV vector through routine optimization. An artisan would have a reasonable expectation of success in optimizing the concentrations because determine method of determining dosage administration schedules (i.e. effective concentration) were long established in the art as demonstrated by Bryne. Thus Bryne renders the instant claims obvious.

No claims are allowed.

Any inquiry concerning this communication or earlier communications from the examiner should be directed to MARCIA STEPHENS NOBLE whose telephone number is (571)272-5545. The examiner can normally be reached M-F 9-5:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Peter Paras can be reached on 571-272-4517. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.

MARCIA S. NOBLE
Primary Examiner
Art Unit 1632

/MARCIA S NOBLE/Primary Examiner, Art Unit 1632