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 .
Election/Restrictions
Applicant’s election without traverse of the species of “before the vector is administered” and NGF as the therapeutic protein in the reply filed on 12 June 2026 is acknowledged.
Claims 6-7, 9-10, 19, 21-25, 27-28, 30-31, 33-35, 37, 39-40, and 43 are cancelled. Claims 1-5, 8, 11-18, 20, 26, 29, 32, 36, 38, 41-42, and 44-45 are pending. Claims 5, 17-18, and 41 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Claims 1-4, 8, 11-16, 20, 26, 29, 32, 36, 38, 42, and 44-45 are being examined on the merits.
Priority
This application is a 371 PCT of US2021/055881 filed 10/20/2021 which claims priority to application 63/104,370 filed 10/22/2020.
Information Disclosure Statement
The information disclosure statements filed 8/28/2023, 10/23/2024, and 2/11/2026 have been considered.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code at paragraph 203. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
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.
Claim 1-4, 8, 11-15, 20, 26, 29, 32, 36, 38, 42, and 44-45 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.
For claims drawn to a genus, MPEP § 2163 states the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, 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 claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
Claim 1 is directed a method for suppressing an immune response to a therapeutic protein encoded by a vector in a subject in need thereof and/or for treating a disease or disorder associated with reduced expression of a therapeutic protein in a subject in need thereof, the method comprising administering to the subject a composition comprising the therapeutic protein or a homolog or functional variant thereof, optionally an immunologically related variant thereof. The claims encompasses methods employing any therapeutic protein; homologs thereof; functional variants thereof; immunologically related variants thereof; antibodies; antigen binding fragments; proteins having at least 95% identity with endogenous proteins; essentially any disease or disorder treatable by gene therapy; and any suitable vector.
The specification, however, provides only a limited number of representative species, principally anti-NGF antibodies, several other antibodies, CD3 bispecific antibody, GLP-1, insulin, GnRH, MIS/AMH, and limited veterinary AAV examples, without representative examples spanning the breadth of the claimed genus. The specification only provides working examples to directed to anti-NGF, a GLP-1, an anti-IL-31. Nor does the specification disclose structural features common to the claimed genus that would allow one of ordinary skill to recognize which therapeutic proteins, homologs, functional variants, or immunologically related variants would successfully suppress an immune response when administered according to the claimed methods.
The breadth of the claimed genus is inconsistent with the state of the art. Hermeling (Hermeling et al. Pharmaceutical research 21.6 (2004): 897-903) teaches that “Examples of how the chemical structure (including amino acid sequence, glycosylation, and pegylation) can influence the incidence and level of antibody formation are given. Moreover, it is shown that physical degradation (especially aggregation) of the proteins as well as chemical decomposition (e.g., oxidation) may enhance the immune response. To what extent the presence of degradation products in protein formulations influences their immunogenicity still needs further investigation.” [abstract]. Hermeling further teaches that “Protein structure is one of the factors that can affect the immune response in man… proteins are complex molecules, so that a small change at a particular site may result in a major change in the overall properties… in general, it is very difficult to relate a particular change in protein structure to a change in immunogenicity.” [Table 1; pg. 899, col. 1, para 2]. Likewise, Rosenberg (Rosenberg. The AAPS journal 8.3 (2006): 59) teaches that: “Other critical factors bearing on immunogenicity of aggregates pertain to both product and host: product origin…, contaminants…, neoepitopes…, glycosylation/pegylation... Host and protocol factors important… include frequency of administration, route of administration, host immune status, concomitant immunomodulators, and… robustness of immunologic tolerance to the endogenous protein.” [pg. E503, col. 1, para 2]. These references demonstrate that immunogenicity depends upon numerous protein-specific structural and biological variables and that no common structural principle was known that would permit extrapolation across essentially every therapeutic protein, homolog, functional variant, and immunologically related variant encompassed by the claims.
8. Accordingly, in view of the limited amount of guidance provided by the specification and the art, one of ordinary skill in the art would conclude that Applicant was not in possession of the claimed invention.
Claims 1-4, 8, 11-15, 20, 26, 29, 32, 36, 38, 42, and 44-45 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 for suppressing an immune response to a therapeutic protein encoded by a vector in a subject in need thereof and/or for treating a disease or disorder associated with reduced expression of a therapeutic protein in a subject in need thereof, the method wherein the therapeutic protein is an anti-NGF, a GLP-1, an anti-IL-31, does not reasonably provide enablement for the method for suppressing any immune response or treating any disease or disorder using any therapeutic protein. 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.
Nature of the Invention
Claim 1 is directed a method for suppressing an immune response to a therapeutic protein encoded by a vector in a subject in need thereof and/or for treating a disease or disorder associated with reduced expression of a therapeutic protein in a subject in need thereof, the method comprising administering to the subject a composition comprising the therapeutic protein or a homolog or functional variant thereof, optionally an immunologically related variant thereof.
State of the Art
Hermeling (Hermeling et al. Pharmaceutical research 21.6 (2004): 897-903) teaches that “Examples of how the chemical structure (including amino acid sequence, glycosylation, and pegylation) can influence the incidence and level of antibody formation are given. Moreover, it is shown that physical degradation (especially aggregation) of the proteins as well as chemical decomposition (e.g., oxidation) may enhance the immune response. To what extent the presence of degradation products in protein formulations influences their immunogenicity still needs further investigation.” [abstract]. Hermeling further teaches that “Protein structure is one of the factors that can affect the immune response in man… proteins are complex molecules, so that a small change at a particular site may result in a major change in the overall properties… in general, it is very difficult to relate a particular change in protein structure to a change in immunogenicity.” [Table 1; pg. 899, col. 1, para 2]. Hermeling teaches that “it is very difficult to draw any general conclusions about the influences of primary structure on the immunogenicity” [pg. 900, col. 1, para 4]. Hermeling also teach that “Aggregates are a decisive factor for an antibody response. Aggregates not only increase the classical immune response in conventional animals but also break immune tolerance in transgenic animals made tolerant for the therapeutic protein” [pg. 902, col. 1, para 2]. Likewise, Rosenberg (Rosenberg. The AAPS journal 8.3 (2006): 59) teaches that “protein product aggregates are potent inducers of immune responses to therapeutic protein products. The extent to which these responses impact on therapy is determined by multiple factors” [pg. E506, col. 2, para 2]. Rosenberg teaches that: “Other critical factors bearing on immunogenicity of aggregates pertain to both product and host: product origin…, contaminants…, neoepitopes…, glycosylation/pegylation... Host and protocol factors important… include frequency of administration, route of administration, host immune status, concomitant immunomodulators, and… robustness of immunologic tolerance to the endogenous protein.” [pg. E503, col. 1, para 2]. Rosenberg also teaches that “The mammalian immune system is not equally tolerant to all endogenous proteins,” and that tolerance depends upon protein abundance and presentation [pg. E503, col. 1, para 2].
Breadth of the claims
The methods employing essentially every therapeutic protein, homolog, functional variant, immunologically related variant, antibody, antigen-binding fragment, and numerous unrelated diseases.
Guidance of the Specification
The specification, however, provides only a limited number of representative species, principally anti-NGF antibodies, several other antibodies, CD3 bispecific antibody, GLP-1, insulin, GnRH, MIS/AMH, and limited veterinary AAV examples, without representative examples spanning the breadth of the claimed genus. The specification only provides working examples to directed to anti-NGF, a GLP-1, an anti-IL-31.
Experimentation Required
Accordingly, a person of ordinary skill in the art seeking to practice the full scope of the claimed invention would be required to determine empirically, for each new therapeutic protein encompassed by the claims: the appropriate protein or variant; whether homologs or immunologically related variants retain tolerogenic properties; formulation; aggregation state; dosing regimen; administration schedule; vector; promoter; route of administration; disease; patient immune status; and whether immune tolerance would actually be induced. The amount of experimentation required is substantial because the specification provides insufficient guidance for predicting which combinations of protein and/or diseases would be required to practice the full scope of the claimed genus. The need for extensive screening and characterization of numerous variants constitutes undue experimentation under the factors set forth in In re Wands, 858 F.2d 731 (Fed. Cir. 1988).
The Supreme Court has further explained that a specification must enable the full scope of the claimed genus. See Amgen Inc. v. Sanofi. Because the present disclosure requires substantial screening to identify operative members of the claimed genus that retain the disclosed binding and signaling activities, the specification does not enable the full scope of claim 1.
Taking into consideration the factors outlined above, including the nature of the invention, the breadth of the claims, the state of the art, the guidance provided by the applicant and the specific examples, it is the conclusion that an undue experimentation would be required to make and use the invention as claimed.
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.
Claims 1-3, 4, 8, 12-13, 26, 29, 32, 38, and 41-42 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Koeberl [US 20110070220 A1].
Regarding claims 1-3, 13, and 29, Koeberl teaches a method for enhancing patient response to therapeutic protein administration by inducing immune tolerance to the therapeutic protein through administration of a vector encoding the same therapeutic protein. Specifically, Koeberl teaches that antibody responses generated against therapeutic proteins reduce the efficacy of protein replacement therapy, and therefore provides an immunomodulatory gene therapy strategy based upon induction of immune tolerance. Koeberl explains that CRIM-negative Pompe patients receiving enzyme replacement therapy (ERT) produce high titers of anti-GAA antibodies that diminish therapeutic efficacy, and states that the invention provides “a strategy for effecting immunosuppression … based … on induction of immune tolerance.” [0025]-[0028]. Koeberl teaches a method of enhancing patient response to protein therapy comprising/treating Pompe disease comprising: i) administering to a patient in need thereof a therapeutic amount of said protein (i.e., GAA), and (ii) administering to said patient an immunosuppressive, subtherapeutic dose (regarding claim 13 and 29) of a vector comprising a nucleic acid sequence encoding said protein (i.e., GAA) operably linked to a liver-specific promoter, wherein said vector is administered under conditions such that the therapeutic effect of said protein is enhanced [0027; claim 1].
Regarding claim 4, Koeberl teaches administration of rhGAA either before (G1), prior to (G2), or simultaneously with (G4) theAAV-LSPhGAApA vector [0019, claim 13].
Regarding claim 8, Koeberl teaches that the AAV-vector mediated gene therapy can induce tolerance to introduced GAA [0009].
Regarding claim 12, Koeberl teaches administration of human GAA for replacement of endogenous GAA deficiency (enzyme replacement therapy (ERT)) and repeatedly explains that immune tolerance is directed toward replacement of the endogenous therapeutic protein [0004, 0006, 0009; claim 1-2]. Therefore, the protein would inherently be recognized by the immune system as self-antigen.
Regarding claim 26, Koeberl teaches that the GAA is administered at a dose of 20mg/kg [0047].
Regarding claim 32, Koeberl teaches titer for mock-treated GAA-KO mice was significantly elevated at 6 months of age, in comparison to AAV vector-treated GAA-KO mice; showing a reduction in antibody formation by more than 20% [0048, FIG. 1B].
Regarding claim 38, Koeberl teaches that the vector is administered at a dose of 1x108 to 1x1012 viral particles/kg body weight [0030].
Regarding claim 41, Koeberl teaches that the protein is administered after the vector is administered.
Regarding claim 42, Koeberl teaches that rhGAA was administered to naive GAA-KO mice that had not received rhGAA previously [0049].
Claims 1-2 and 13-16 and 45 are rejected under 35 U.S.C. 102(a)(1) as being anticipated Koeberl [US 20110070220 A1] in view of Lacy (US 2016/0264656 A1).
Lacy teaches a method of treating (e.g., curing, suppressing, ameliorating, delaying or preventing or decreasing the risk of the onset, recurrence or relapse of) or preventing an NGF associated disorder, in a subject. The method includes: administering to the subject a disclosed NGF binding protein (particularly an antagonist), e.g., an anti-NGF antibody or fragment thereof as described herein, in an amount sufficient to treat or prevent the NGF associated disorder. The NGF antagonist, e.g., the anti-NGF antibody or fragment thereof, can be administered to the subject, alone or in combination with other therapeutic modalities as described herein [0372].
Regarding claim 13, Lacy teaches such compositions can be used for example in a method for treating a mammal for a disease or disorder involving increased levels of NGF by administering to the mammal an effective amount of the composition [0376].
Regarding claim 26, Lacy teaches administering the dose of 0.001 to about 20 mg/kg [0418].
Regarding claim 45, Lacy teaches that the Non-limiting examples of NGF-related diseases and disorders include gout joint pain and osteoarthritis [0374].
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 1-4, 8, 11-13, 20, 26, 29, 32, 38, 42, and 44 are rejected under 35 U.S.C. 103 as being unpatentable over Koeberl [US 20110070220 A1].
Regarding claims 1-3, 13 and 29, Koeberl teaches a method for enhancing patient response to therapeutic protein administration by inducing immune tolerance to the therapeutic protein through administration of a vector encoding the same therapeutic protein. Specifically, Koeberl teaches that antibody responses generated against therapeutic proteins reduce the efficacy of protein replacement therapy, and therefore provides an immunomodulatory gene therapy strategy based upon induction of immune tolerance. Koeberl explains that CRIM-negative Pompe patients receiving enzyme replacement therapy (ERT) produce high titers of anti-GAA antibodies that diminish therapeutic efficacy, and states that the invention provides “a strategy for effecting immunosuppression … based … on induction of immune tolerance.” [0025]-[0028]. Koeberl teaches a method of enhancing patient response to protein therapy comprising/treating Pompe disease comprising: i) administering to a patient in need thereof a therapeutic amount of said protein (i.e., GAA), and (ii) administering to said patient an immunosuppressive, subtherapeutic dose (regarding claim 13 and 29) of a vector comprising a nucleic acid sequence encoding said protein (i.e., GAA) operably linked to a liver-specific promoter, wherein said vector is administered under conditions such that the therapeutic effect of said protein is enhanced [0027; claim 1].
Although Koeberl specifically exemplifies GAA, it expressly teaches that the immunomodulatory strategy is applicable broadly to disorders treated with infused proteins, including lysosomal storage diseases, hemophilia, adenosine deaminase deficiency, alpha-1 antitrypsin deficiency, growth hormone deficiency, insulin-dependent diabetes, gout treated with uricase, and even peptide antigens associated with allergy [0073]. This demonstrates that the immune-tolerance protocol is not limited to GAA.
One of ordinary skill in the art would have been motivated, before the effective filing date of the claimed invention, to employ Koeberl’s immune-tolerance protocol whenever administration of a therapeutic protein was expected to elicit anti-drug antibodies because Koeberl expressly teaches that the strategy broadly applies to therapeutic proteins whose efficacy is compromised by antibody formation. Extending the same protocol to additional therapeutic proteins would merely constitute the predictable use of a known immune-modulation technique according to its established function.
Regarding claim 4, Koeberl teaches administration of rhGAA either before (G1), prior to (G2), or simultaneously with (G4) theAAV-LSPhGAApA vector [0019, claim 13].
Regarding claim 8, Koeberl teaches that the AAV-vector mediated gene therapy can induce tolerance to introduced GAA [0009].
Regarding claim 11-12, Koeberl teaches administration of human GAA for replacement of endogenous GAA deficiency (enzyme replacement therapy (ERT)) and repeatedly explains that immune tolerance is directed toward replacement of the endogenous therapeutic protein [0004, 0006, 0009; claim 1-2]. Although Koeberl does not explicitly recite “95% identity,” human recombinant GAA is the endogenous replacement protein, rendering this limitation at least obvious. Therefore, the protein would inherently be recognized by the immune system as self-antigen.
Regarding claim 20, Koeberl teaches that the method is used for enhancing the response of a Pompe disease patient to ERT and that human studies have suggested that antibody formation to rhGAA reduced the efficacy of ERT [claim 18; 0006]. Therefore, it would have been obvious that the method involved delivery to a human in need thereof.
Regarding claim 26, Koeberl teaches that the GAA is administered at a dose of 20mg/kg [0047].
Regarding claim 32, Koeberl teaches titer for mock-treated GAA-KO mice was significantly elevated at 6 months of age, in comparison to AAV vector-treated GAA-KO mice; showing a reduction in antibody formation by more than 20% [0048, FIG. 1B].
Regarding claim 38, Koeberl teaches that the vector is administered at a dose of 1x108 to 1x1012 viral particles/kg body weight [0030].
Regarding claim 42, Koeberl teaches that rhGAA was administered to naive GAA-KO mice that had not received rhGAA previously [0049].
Regarding claim 44, the teachings of Koeberl are discussed above as applied to claim 4. Since the therapeutic protein is delivered before the administration of the vector, one of ordinary skill in the art would have understood that expression of this protein would necessarily occur before expression of an AAV-delivered transgene which requires cellular uptake, second-strand synthesis, transcription and translation after administration.
Claims 14-16 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Koeberl [US 20110070220 A1] in view of Lacy (US 2016/0264656 A1).
The teachings of Koeberl are discussed above as applied to claim 1 and similarly apply to claims 14-16 and 45.
Koeberl do not teach where the therapeutic protein is a monoclonal antibody that binds nerve growth factor (NGF) and the disease is degenerative joint disease (DID).
Lacy teaches a method of treating (e.g., curing, suppressing, ameliorating, delaying or preventing or decreasing the risk of the onset, recurrence or relapse of) or preventing an NGF associated disorder, in a subject. The method includes: administering to the subject a disclosed NGF binding protein (particularly an antagonist), e.g., an anti-NGF antibody or fragment thereof as described herein, in an amount sufficient to treat or prevent the NGF associated disorder. The NGF antagonist, e.g., the anti-NGF antibody or fragment thereof, can be administered to the subject, alone or in combination with other therapeutic modalities as described herein [0372].
Regarding claim 45, Lacy teaches that the Non-limiting examples of NGF-related diseases and disorders include gout joint pain and osteoarthritis [0374].
One of ordinary skill in the art would have been motivated, before the effective filing date of the claimed invention to apply Koerberl’s immune tolerance strategy to anti-NGF antibody therapy in osteoarthritis patients to reduce anti-drug antibody formation and improve therapeutic efficacy. One of ordinary skill would be motivated to make the modification Korbel teaches that therapeutic proteins are susceptible to anti-drug immune response and teaches that the efficacy of ERT can also be utilized in other disorders that are complicated by immune response [0037-0073].
Claim 36 is rejected under 35 U.S.C. 103 as being unpatentable over Koeberl (US 20110070220 A1) as applied to claims 1 and 8, and further in view of Wang (Wang et al. Gene therapy 10.17 (2003): 1528-1534).
The teachings of Koeberl are discussed above as applied to claims 1 and 8 and similarly apply to claim 36.
Koeberl do not teach where the vector is AAV1.
Wang teaches that recently, gene transfer vectors based upon other AAV serotypes (1 and 3–8) have been developed; and that in vivo investigations have shown that these vectors differ in their ability to transduce specific cell types and organs (i.e., different tropism) [pg. 1528, col. 1-2, bridging paragraph]. Wang teaches that rAAV1 vector (rAAV1-GFP) had a 13- to 35-fold greater transduction efficiency than that of the rAAV2 vector (rAAV2-GFP) [abstract].
It would have been obvious before the effective filing date of the claimed invention to substitute the AAV2 vector of Koeberl for the AAV1 vector of Wang. One of ordinary skill would be motivated to make the modification because Wang teaches that AAV1 was a known recombinant gene therapy vector with the advantage of improved transduction characteristics and distinct tissue tropism. Selection of an appropriate AAV vector for delivery is recognized as routine optimization based on the desired transduction characteristics of the target tissue, and such substitution would have represented the predictable use of one known AAV serotype in place of another to achieve the expected result of greater effective gene delivery.
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY N GROOMS whose telephone number is (571)272-3771. The examiner can normally be reached M-F 830-530.
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/TIFFANY NICOLE GROOMS/Examiner, Art Unit 1637
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