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Patent Application 16625381 - METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE - Rejection

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Patent Application 16625381 - METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE

Title: METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF FIBROSIS WITH AGENTS CAPABLE OF INHIBITING THE ACTIVATION OF MUCOSAL-ASSOCIATED INVARIANT T (MAIT) CELLS

Application Information

  • Invention Title: METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF FIBROSIS WITH AGENTS CAPABLE OF INHIBITING THE ACTIVATION OF MUCOSAL-ASSOCIATED INVARIANT T (MAIT) CELLS
  • Application Number: 16625381
  • Submission Date: 2025-05-13T00:00:00.000Z
  • Effective Filing Date: 2019-12-20T00:00:00.000Z
  • Filing Date: 2019-12-20T00:00:00.000Z
  • National Class: 424
  • National Sub-Class: 154100
  • Examiner Employee Number: 79112
  • Art Unit: 1641
  • Tech Center: 1600

Rejection Summary

  • 102 Rejections: 0
  • 103 Rejections: 2

Cited Patents

No patents were cited in this rejection.

Office Action Text


    RESPONSE TO APPLICANT’S AMENDMENT

1.  Applicant's amendment, filed 04/23/2025, is acknowledged.

2.  Claims 1, 5-6, 12-13, 15, 17, 19-20 and 22-24 are pending.

3.  Claim 17 stands withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.

4. Claims 1, 5-6, 12-13, 15, 19-20 and 22-24 are under examination as they read on  the species: 1) anti-MR1 antibody, and (2) liver fibrosis.

 5.  The following new grounds of rejections are necessitated by the amendment submitted 04/23/2025.

6.  The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof. 

The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.  The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph, is invoked. 
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph:
(A)	the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function; 
(B)	the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and 
(C)	the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function. 

Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function. 

Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function. 

Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.

7.  This application includes one or more claim limitations that use the word “means” or “step” but are nonetheless not being interpreted under 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph because the claim limitation(s) recite(s) sufficient structure, materials, or acts to entirely perform the recited function.  Such claim limitation(s) is/are: “antibody comprising means for binding human MHC-related protein 1 (MR1)” in independent claims 1 and 20.

Specifically, with regard to the “three prong test”, both independent claims recite “means” and thus prong “A” is satisfied.  Further, both independent claims recite the functional language of “binding for binding MR1” and thus satisfy prong B.  However, the claims do not satisfy prong C which requires that “the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.”  This is because both independent claims modify the “means for binding” to necessarily have the structure of being an antibody.  Thus, the claims do provide structural limitations concerning the “means” that is binding a human MR1 so that it is not generic.  For example, the endogenous receptor for the human MR1 is Vα7.2-Jα33 receptor (US 20170209442, of record).  However, the Vα7.2-Jα33 receptor cannot serve as a “means for binding” human MR1 even though it very clearly doses bind MR1 because it is not an antibody as is required by the independent claims.  Therefore, it is clear that the recited “means” is modified by the structure of having to be an antibody rather than being a “generic” means with no structural limitations as 35 USC 112(f) requires. 
    
Because this/these claim limitation(s) is/are not being interpreted under 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph, it/they is/are not being interpreted to cover only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof.

If applicant intends to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA  35 U.S.C. 112, sixth paragraph, applicant may:  (1) amend the claim limitation(s) to remove the structure, materials, or acts that performs the claimed function; or (2) present a sufficient showing that the claim limitation(s) does/do not recite sufficient structure, materials, or acts to perform the claimed function.


8. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA  35 U.S.C. 112, first paragraph):
(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.

9.  Claims 1, 5-6, 12-13, 15, 19-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), as containing 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(s), at the time the application was filed, had possession of the claimed invention. This is a New Matter rejection. 

The phrase “an antibody comprising means for binding human MHC-restated protein 1 (MR1)” and “an antibody comprising means for binding MR1” claimed in claims 1 and 20, represents a departure from the specification and the claims as originally filed for the same reasons set forth in the previous Office Action mailed 01/27/2025.
  
Applicant’s arguments, filed 04/23/2025, have been fully considered, but have not been found convincing.

Applicant submits that the specification discloses the publicly available anti-MR1 antibody clone 26.5.  Applicant concluded that the “means plus” language of the present claims encompass clone 26.5 and equivalents thereof.

The Examiner agrees with Applicant’s interpretation of the claims; however, the issue here is the specification does not provide a clear support of for the functionally equivalents to clone 26.5.  The amended claims narrow the claim to a subgenus of antibodies comprising means for binding “human MR1” in claim 1 or means for binding “MR1” in claim 20  and the specification fails to contemplate a functionally equivalents to clone 26.5.   The instant claims now recite limitations which were not clearly disclosed in the specification and recited in the claims as originally filed.

10.  Claims 1, 5-6, 12-13, 15, 19-20 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 pre-AIA  the inventor(s), at the time the application was filed, had possession of the claimed invention.

Claims 1 and 20 is drafted in a means-plus-function limitation.  The limitations are interpreted to cover the structure or acts disclosed in the specification to perform the recited functions, and equivalents thereof. 

Applicant has broadly claimed methods of administering antibodies to treat liver fibrosis that a) bind the human MHC-related protein 1 (MR1) via a “means for binding”.   Note that as discussed earlier in this office action under 35 USC 112(f), the recited “means for binding” IS structurally modified by the requirement that it be an antibody.  This means that the term is NOT being interpreted to cover only the corresponding structure, material, or acts described in the specification as performing the claimed function, and equivalents thereof.  It should; also be pointed out that no experimental data from working examples using antibodies binging the human MR1 via a “means for binding” are provided in the instant specification.  This section discloses prior art antibodies suitable for administration in the disclosed methods as evidenced by the following quotes under DNA synthesis assay (page 15): 


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Further, Lamichhane and Ussher (Immunology, 151, 270–279, 2017) teach that several studies have assessed the expression of MR1 protein. Using anti-MR1 antibody 26.5, which only recognizes MR1 in a folded (presumed to be ligand-bound) form.  Thus, the only antibody species explicitly disclosed in the instant specification appear to be recognize MR1 in a folded form (i.e., conformational epitope).  Clone 26.5 is conformational antibody.  Moreover, Lamichhane et al teaches that  26.5 antibody is both agonist and antagonist ligand (see page 274, left col., 1st ¶).

With respect to a conformational epitope, conformational epitope is formed of amino acid residues that are discontinuous in the protein sequence but which are brought together upon folding of the MR1 protein into its three-dimensional structure. The conformational epitope differs from a linear epitope, which is formed by a continuous sequence of amino acids in the MR1 protein.  

The guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, § 1 "Written Description" Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus.  See MPEP 2163.  In The Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F. 3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted: “A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. See Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin [e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). Accordingly, naming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.” The court has further stated that “Adequate written description requires a precise definition, such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.” Id. at 1566, 43 USPQ2d at 1404 (quoting Fiers, 984 F.2d at 1171, 25 USPQ2d at 1606). Also see Enzo-Biochem v. Gen-Probe 01-1230 (CAFC 2002). Recent court cases have emphasized the need for correlation between a well-defined structure and recited functional limitations. For example, the courts have indicated that recitation of an antibody which has specific functional properties in the absence of knowledge of the antibody sequences that give rise to said functional properties do not satisfy the requirements for written description. See for example AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) as well as Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017). Indeed, in Amgen the court indicates that that it is improper to allow patentees to claim antibodies by describing something that is not the invention, i.e. the antigen, as knowledge of the chemical structure of an antigen does not give the required kind of structure-identifying information about the corresponding antibodies, with the antibody-antigen relationship be analogized as a search for a key on a ring with a million keys on it.  As such, knowledge of one part if a binding pair (such as antibody-antigen or ligand-receptor) fails to provide information as to what the other member of the binding interaction necessarily looks like (i.e. its primary amino acid structure). Applicant is reminded that the courts have long ruled that “Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features.” See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. As such, disclosure of a screening assay to test for functional properties of an antibody (such as binding to receptor A but not receptor B, etc.) does not provide evidence of possession of the antibody itself.

The antibodies administered in the instant claimed treatment methods have the following functional properties binding conformational human MR1 via the antigen binding domain. No structure recited in the claims for the antigen binding domain, namely a VH and VL pair sufficient to provide for the function of integrin binding. 

Besides Clone 26.5, there does not appear to be any data or teachings that the antibodies species disclosed in the specification fail to have the instant recited functional properties.  

Applicant’s arguments, filed 04/23/2025, have been fully considered, but have not been found convincing.

Applicant submits that the amended claims recite “means for binding MR1” language which encompass clone 26.5 and equivalents thereof. Applicant points to Ex Parte Chamberlian, the written description requirement for antibodies may be satisfied through the use of means plus language.  The present claims would thus encompass the anti-MR1 antibody clone 26.5 disclosed in the present application and equivalents thereof. 

This is not found convincing because the as discussed under 35 USC 112(f), the recited “means for binding” IS structurally modified by the requirement that it be an antibody. Ex Parte Chamberlian does not apply.  The claims encompass a genus of antibodies while the specification discloses only a single member of a genus (clone 26.5) did not provide adequate written support for the claimed genus.

11.  Claims 1, 5-6, 12-13, 15, 19-20 and 22-24 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 a method of treating liver fibrosis in a patient in need thereof comprising administering to the patient anti-MR1 antibody, clone 26.5 (once deposit of the clone is satisfied) , does not reasonably provide enablement for claimed methods treating a genus of fibrosis with a genus of gents capable of inhibiting the activation of MAIT cells.  The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims for the same reasons set forth in the previous Office Action mailed 07/08/2024,  09/16/2024 and 01/27/2025.

Applicant submits that the claims are amended to recite “means for binding MR1”.  As acknowledged by the Examiner, the specification discloses the publicly available anti-MR1 antibody clone 26.5. Thus, the “means plus” language of the present claims encompass clone 26.5 which the Examiner considers to be enabled and equivalents thereof.

As discussed in previous responses, the present application shows that an anti-MR1 antibody (26.5) capable of binding MRI significantly inhibited MAIT cell-induced proliferation of myofibroblasts (Figure 1A).

Also as previously discussed, the post-filing article by the inventors (Mabire et al. submitted with the response filed May 28, 2024) demonstrated in vivo use of an anti-MRI antibody to treat fibrosis. As stated on page 3, last paragraph, “Beneficial impact of    a MR1-blocking strategy was further confirmed with a monoclonal neutralizing antibody    to MRI. Injection of the MR1 antibody to mice with established fibrosis for 4 days after    the last CC14 injection decreased MAIT cell activation, as reflected by reduced frequency    of CD69+ MAIT cells (Fig. $3d) while it did not affect MAIT cell frequency (Fig. S3e).    Mice injected with the MR1 antibody showed decreased Sirius red staining compared to    mice injected with isotype (Fig. 2g). Taken together, these data demonstrate through two    different, pharmacological and antibody-driven, approaches the beneficial impact of    MAIT cell inhibition on fibrosis regression.” Although part of the non-elected species, it    is noted that a small molecule (Ac-6-FP) was also demonstrated to be effective (see    Figures 2A-B) of Mabire et al. submitted with the response filed May 28, 2024.

The Mabire et al reference (Nature Communications, 14:1830, 2023) is sufficient to enable clone 26.5 anti-MR1 antibody in the treatment of liver fibrosis but not sufficient to enable the genus of anti-MR1 antibodies claimed.  Mabire et al demonstrate liver fibrosis regression by the administration of anti-MR1 antibody, clone 26.5.

It remains that the claims are directed to a broad class of antibodies the ability to bind MR1 and treat liver fibrosis. However, the specification did not give the skilled in the art enough information to choose candidate antibodies from the millions of options and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”

The specification discloses only one species of anti-MRI antibodies; while the claims are directed to a genus of millions anti-MAIT antibodies.

In Sanofi-Aventisub, the Federal Circuit relied on its prior precedential opinions when determining whether the full scope of a genus was enabled. These decisions included McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091 (Fed. Cir. 2020) (hereafter McRO); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380 (Fed. Cir. 2013) (hereafter Wyeth); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019) (hereafter Enzo); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149 (Fed. Cir. 2019) (hereafter Idenix).


12.  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.

13.  Claims 1, 5-6, 12-13, 15, 20 and 23-24  are rejected under 35 U.S.C. 103 as being unpatentable over Sa et al (Journal of Immunology, (May 2017)   198(1), Supp. 1, Abs: 65.12) or  Riva et al (Journal of Hepatology, (April 2015) 62(2):S206. Abstract: 0034), each in view of US 20170209442 for the same reasons set forth in the previous Office Action mailed 01/27/2025.

14.  Claims 19 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Sa et al (Journal of Immunology, (May 2017)   198(1), Supp. 1, Abs: 65.12) in view of US 20170209442, as applied to claims 1, 5-6, 12-13, 15, 20 and 23-24, above and further in view of Owens et al (1994) for the same reasons set forth in the previous Office Action 01/27/2025.


Applicant’s arguments, filed 04/23/2025, have been fully considered, but have not been found convincing.

 Applicant submits that amended claims replace “means for inhibiting the activation of MAIT cells” with and equivalents thereof. Applicant submits that Sa et al. teaches that the percentage of circulating MAIT cells is “severely reduced” in alcoholic liver disease (ALD) patients. Sa further teaches that the remaining cells display an increased expression level of activation markers. However, Sa does not teach or suggest that agents capable of inhibiting the activation of MAIT cells or anti- MRI antibodies would be useful for the treatment of liver fibrosis. Indeed, fibrosis is not mentioned at all in the document.  Further Applicant submits that the Examiner relies on Riva as teaching that MAIT cells are a target for ALD.    However, like Sa, Riva also does not mention fibrosis and does teach or suggest that    agents capable of inhibiting the activation of MAIT cells would be useful for the    treatment of liver fibrosis. Moreover, a subsequent publication from Riva et al. in 2016 discusses similar results and indicates that “MAIT reactivation via modulation of the gut flora may be a promising immunotherapeutic target for ALD” (emphasis added; last    sentence). Thus, it would be clear to one of ordinary skill in the art that the targeting of    MAIT cells as suggested by Riva is for reactivation and not inhibition of activation.  Applicant also submits that the US 20170209442 does not compensate for the deficiencies of Sa as this reference  was only relied upon for teaching agents which bind MRI and is primarily focused on  small molecules. US 20170209442 does not teach that any of the disclosed antibodies would be useful for inhibiting the activation of MAIT cells (Figure 19 cited by the Examiner refers to cell accumulation, not activation). US 20170209442 is also silent  regarding the treatment of liver fibrosis.  Owens does not compensate for the deficiencies of Sa and US 20170209442 as    this reference was only relied upon for teaching methods of humanization of antibodies. Therefore, the claimed invention is not obvious over the cited references.   Reconsideration and withdrawal of this rejection is thus respectfully requested.

However, given Sa et al teaching that activated MAIT cell population in the liver contributes to the pathogenesis of ALD including patients with steatohepatitis (ASH), steatohepatitis with cirrhosis (ASHAC) and cirrhosis (AC) and Riva et al teachings that MAIT cells may represent a novel immunotherapeutic target for ALD,  it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the inhibitory ligands /anti-MR1 antibody which bind to MR1, clone 26.5, which block MR1 to bind to MAIT cells thereby inhibiting MAIT cell activation taught by the `442 publication which contribute to the pathogenesis of ALD taught by Sa et al.


15.  No claim is allowed.


16.  Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action.  Accordingly, THIS ACTION IS MADE FINAL.  See MPEP § 706.07(a).  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 extension fee 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 date of this final action. 

17.  Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.

Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). 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) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.

May 6, 2025
/MAHER M HADDAD/            Primary Examiner, Art Unit 1644                                                                                                                                                                                            



    
        
            
        
            
        
            
        
            
        
            
        
            
        
            
    


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