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 .
This action is in response to the papers filed December 31, 2025.
Claims 16-33 are pending in the application.
Applicant’s election without traverse of a transgene encoding CILP-1 (claims 16, 18-20, 23, and 25-33) in the reply filed on 12/31/2025 is acknowledged.
Claims 17, 21-22, and 24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 12/31/2025.
Therefore, claims 16, 18-20, 23, and 25-33 are examined on the merits.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/EP2021/065424 filed June 09, 2021.
Applicant’s claim for the foreign benefit of a prior-filed European Patent 20305625.4 filed June 09, 2020 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is June 09, 2020.
Specification
The disclosure is objected to because of the following informalities:
Paragraph 0173 has “(Erreur ! Source du renvoi introuvable.)” within it, which seems to be an error in the translation of the document to English as the reference previously stated not being found.
Paragraph 00051 misspells CILP-1 as “CLIP-1” at the last line of page 13. This indicates a completely separate protein.
Appropriate correction is required.
Claim Objections
Claim 20 is objected to because of the following informalities: the first time an acronym is utilized in a claim-set, said acronym should be spelled out in its entirety followed by said acronym in parenthesis (e.g. Cartilage intermediate layer protein (CILP-1)).
Appropriate correction is required.
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.
Claims 16, 18-20, 23, and 25-33 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 reducing heart fibrosis via intravenous administration of an AAV9 vector with a hTnn2 promoter encoding a transgene to overexpress CILP, WISP2, DKK3 or SFRP2 at an effective dosage of 1 x 1013 vg/kg to a patient in need thereof,
does not reasonably provide enablement for
a method of treating genetic dilated cardiomyopathies in a patient in need thereof, comprising administering any dosage via any administration route to the patient of any expressible modulator of the Wnt or TGF-3 pathway
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.
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 have required 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 or use the invention based on the content of the disclosure is “undue” (In re Wands, 858 F.2d 731, 737, 8 USPQ2ds 1400, 1404 (Fed. Cir. 1988)).
The Breadth of the Claims and The Nature of the Invention
The independent claim is directed to a method of treating a subject having any genetic dilated cardiomyopathy, the method comprising the step of administering any modulator of the Wnt or TGF-beta pathway at any dosage by any route of administration, thereby treating the subject.
While the specification discloses the pharmaceutical composition “may be administered by any convenient route, such as in a non-limiting manner by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.) and administration can be systemic, local, or systemic combined with local; systemic includes parenteral and oral, and local includes local and loco-regional. Systemic administration is preferably parenteral such as subcutaneous (SC), intramuscular (IM), intravascular such as intravenous (IV) or intraarterial; intraperitoneal (IP); intradermal (ID), epidural or else” (para. 000151), such is non-limiting.
The claims are broad for reasonably encompassing a multitude of anatomically and physiologically distinct administration routes, including, but not limited to, delivery and administration systemically, regionally or locally, or by any route, for example, by injection, infusion, orally, ingestion, inhalation, intranasal, intubation, intrapulmonary, intrapulmonary instillation, subcutaneously, and others.
No administration routes are recited in the claims, let alone the independent claim.
The claims are broad for reasonably encompassing a multitude of AAV capsid serotypes, including AAV1, AAV2, AAV3 (including types3A and 3B), AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV2i8, AAVrh10, AAVrh39, AAVrh43, AAVrh74, AAV-LK03, AAV2G9, AAV.PHP, AAV-Anc80, AAV3B and AAV9.rh74 (para. 00123).
Claim 30 recites a broad list of AAV capsids.
Claim 31 recites AAV9.rh specifically.
The claims are broad for reasonably encompassing any expressible modulator of TGF-beta or WNT pathways. As disclosed in para. 0030 and 0031. This includes both activators and inhibitors. Moreover, it includes “ribonucleic acid (RNA) molecule or a protein, polypeptide or peptide. The invention encompasses in particular RNA molecule inhitors such as interfering RNAs (siRNA, shRNA), CRISPR guide RNAs, ribozymes and aptamers targeting components of the Wnt or TGF- R pathway. The invention encompasses also protein, polypeptide or peptide modulators such as components of the Wnt or TGF- R pathway, variants or derivative thereof (fragments, fusion proteins ; decoy receptors, soluble proteins, dominant negative mutants) and antibodies directed to components of the Wnt or 15TGFR pathway including fragments and expressible derivative thereof” as well as transgenes specifically (para. 0021, 0031).
The species election has directed the claims to a transgene.
The claims are broad for reasonably encompassing any dosage of AAV vector or modulator of the pathways. The specification only discloses dosages within the working examples of 1011 vg/mouse equivalent to 1013 vg/kg in a 20 g mouse (para. 0233).
The State of the Prior Art, The Level of One of Ordinary Skill and The Level of Predictability in the Art
Considering the mode of administration, the specification simply requires administration of the AAV to the subject by any means and any dosage. The art has demonstrated through numerous publications, delivery of nucleic acid vectors in vivo is highly unpredictable for successful human therapy.
Daya et al (Gene Therapy Using Adeno-Associated Virus Vectors, Clin. Microbiol. Rev. 21(4): 583-593, 2008; p. 590-591, joining ¶). When considering AAV therapy, there are many obstacles to its use systemically- host cell immune response which leads to toxicity (Daya et al, p. 587, col 2), blood brain as well as cellular barriers against the virus, adequate expression, degradation of the vector or the product. Even the use of targeting methods and tissue specific promoters have done little to overcome the numerous obstacles related to gene delivery. Even use of tissue specific promoters and capsids targeting has not successfully overcome these obstacles. Taken together with the large breadth of target tissues and diseases claimed, in light of the difficulties to overcome even one of these barriers, one could not perform the full breadth of the claims.
Therefore, it would be undue experimentation to utilize any means of administration with any dosage.
Tian et al (Aerosol Inhalation-mediated Delivery of an Adeno-associated Virus 5-expressed Antagonistic Interleukin-4 Mutant Ameliorates Experimental Murine Asthma, Archives of Medical Research 50: 384-392, 2019) is considered relevant art for having taught inhaled administration of rAAV, whereupon AAV vector DNA was detected in the lung, but not detected in other organs, such as heart, liver, kidney, brain, lymph nodes, and gonads (e.g. Abstract; p. 386, col. 2).
Therefore, administration routes such as inhalation would not be enabled for the present invention which targets the heart.
The Existence of Working Examples and The Amount of Direction Provided by the Inventor
The independent claims fail to recite the minimal AAV dosage required to achieve the therapeutic result.
The specification only discloses dosages within the working examples of 1011 vg/mouse equivalent to 1013 vg/kg in a 20 g mouse administered intravenously (para. 0233). The modulators administered are AAV9-hTnnt2-hCILP, AAV9-4inlshRNA-mLTBP2- GFP, AAV9- hTnnt2-hWISP2, AAV9-hTnnt2-hDKK3 and AAV9-hTnnt2-hSFRP2 (para. 00226, 00233)
The claims fail to recite, and the specification fails to disclose, a first modulator dosage administered via a first administration route, e.g. intravenously, that is necessarily and predictably able to treat dilated genetic cardiomyopathy, as opposed a second dosage administered via a second administration route, e.g. intranasally, that is unable to treat genetic dilated cardiomyopathy, for example.
The therapeutic effect not recited in the claims is reduction of heart fibrosis in vivo (para. 00239).
The Quantity of Any Necessary Experimentation to Make or Use the Invention
Thus, the quantity of necessary experimentation to make or use the invention as claimed, based upon what is known in the art and what has been disclosed in the specification, will create an undue burden for a person of ordinary skill in the art to demonstrate that the broadly claimed genus of rAAV serotypes, broadly claimed dosage which may be administered by the broadly encompassed administration routes so as to necessarily and predictably broadly treat any genetic dilated cardiomyopathy.
Those of ordinary skill in the art would immediately recognize that the instant specification fails to establish the nexus between the broad genus of AAV vectors, the enormous genus of AAV vector dosages, and the corresponding enormous genus of anatomically distinct administration routes so as to necessarily and predictably achieve a real-world, clinically meaningful therapeutic result in subjects with any genetic dilated cardiomyopathy.
In conclusion, the specification fails to provide any guidance as to how an artisan would have dealt with the art-recognized limitations of the claimed method commensurate with the scope of the claimed invention and therefore, limiting the claimed invention to a method of reducing heart fibrosis via intravenous administration of an AAV9 vector with a hTnn2 promoter encoding a transgene to overexpress CILP, WISP2, DKK3 or SFRP2 at an effective dosage of 1 x 1013 vg/kg to a patient in need thereof, is proper.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 28-29 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 28 and 29 recite phrases such as “which comprises an AAV particle” or “which comprises a particle” which render the claim indefinite. It is unclear whether this is referring to the modulator or vector.
It is suggested that the claims be amended as in the subsequent claims of 30 and 31 utilizing the “and wherein” language at line 2 to better specify the invention.
Therefore, claims 28 and 29 are rejected as being indefinite.
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 16, 18-20, 23, 27-30, and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Journal of Molecular and Cellular Cardiology Volume 116, March 2018, Pages 135-144) in view of Zhou (Biomed Res Int. 2015 Oct 4;2015:163564).
Regarding claim 16, 19 and 23, Zhang teaches administering an AAV9 vector comprising a transgene encoding CILP-1 to a mouse model created through Transverse Aortic Constriction (TAC) to demonstrate CILP-1 alleviation of ventricular remodeling and dysfunction (p. 138, 2nd column). Zhang further teaches that C-CILP-1 (a fragment) and full length CILP produced inhibitory effects on TGF-β1 (p. 138, last paragraph; p. 143, 1st paragraph “TGF-β1-induced Smad3 phosphorylation was attenuated by the conditioned medium containing full-, N-, or C-CILP-1 (Fig. 5A)”).. Therefore, CILP-1 has a natural mechanism to modulate/inhibit the TGF-β pathway.
However, Zhang does not teach that it is administered to a patient in need thereof who has genetic dilated cardiomyopathies.
Zhou teaches dilated cardiomyopathy (DCM) is characterized by left ventricular dilation and mutations in the protein Titin (TTN) causing truncations are the leading genetic cause of DCM in human patients (p. 1, 1st paragraph-3rd paragraph).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer CILP-1 in an AAV9 vector as taught by Zhou to a subject with genetic dilated cardiomyopathy as taught by Zhou with a reasonable expectation of success. An artisan would be motivated to do so, as Zhang teaches CILP-1 attenuates ventricular remodeling and dysfunction, a symptom of the genetic dilated cardiomyopathy as taught by Zhou.
Regarding claim 18, the combination of Zhang and Zhou make obvious the method of claim 16. Moreover, Zhang teaches CILP-1 (the modulator, target transgene) modulates the expression CILP-1 attenuate Smad3 phosphorylation, myofibroblasts differentiation, and gene expression of profibrotic molecules (target genes) and “CILP-1 is an active participant in hypertrophic response might arise by its ablation effect on TGF-β1 signaling” (p.143, 1st paragraph).
Regarding claim 20, the combination of Zhang and Zhou make obvious the method of claim 16. Moreover, Zhang teaches the AAV9 vector encoding a CILP-1 transgene and results in the overexpression of said CILP-1 gene (p. 138, 1st column). Therefore, it is an activator of CILP-1.
Regarding claims 27-30, the combination of Zhang and Zhou make obvious the method of claims 16 and 20. Moreover, Zhang teaches the AAV9 vector encoding a CILP-1 transgene for gene therapy (p. 138, 1st column).
Regarding claims 32-33, the combination of Zhang and Zhou make obvious the method of claim 16. Moreover, Zhou teaches a mouse model with a mutation in titin which is associated with genetic cardiomyopathy (p. 1, 3rd paragraph).
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claims 25 and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Journal of Molecular and Cellular Cardiology Volume 116, March 2018, Pages 135-144) in view of Zhou (Biomed Res Int. 2015 Oct 4;2015:163564) as applied to claims 1 and 20 above, and in further view of Heckmann (Gene Therapy volume 23, pages 673–679 (2016)).
As discussed above and incorporated here in its entirety, the combined teachings of Zhang and Zhou make obvious a method of administering a AAV9 vector encoding CILP-1 to a patient having genetic dilated cardiomyopathy.
However, regarding claims 25 and 26, Zhang and Zhou do not teach a specific cardiac promoter such as human cardiac troponin T promoter within the vector.
Heckmann teaches human troponin T promoters are utilized for cardiac specific expression (p. 676, 2nd column). Moreover, Heckmann discusses a separate AAV9/troponin T promoter approach in a murine model of young mice which enables a higher transduction efficiency and could potentially prevent progressive cardiac damage during adolescence (p. 677, 1st column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to modify the AAV9 vector taught by Zhang to a subject with genetic dilated cardiomyopathy to comprise a human troponin T promoter as taught by Heckmann with a reasonable expectation of success. An artisan would be motivated to do so, as Heckmann demonstrates that the utilization of AAV9 and troponin T promoters are known in the art for cardiac specific expression of genes.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Claims 31 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (Journal of Molecular and Cellular Cardiology Volume 116, March 2018, Pages 135-144) in view of Zhou (Biomed Res Int. 2015 Oct 4;2015:163564) as applied to claims 16 and 20 above, and in further view of Duan (Molecular Therapy Vol. 26 No 10 October 2018) and Choi (Current Gene Therapy, 2005, 5, 299-310).
As discussed above and incorporated here in its entirety, the combined teachings of Zhang and Zhou make obvious a method of administering a AAV9 vector encoding CILP-1 to a patient having genetic dilated cardiomyopathy.
However, regarding claim 31, Zhang and Zhou do not teach that the capsid proteins are derived from the AAV9.rh74 serotype.
Duan teaches that clinical trials utilize AAV9 serotypes and AAVrh74 serotypes for gene therapy of Duchene Muscular Dystrophy (Table 5).
Choi teaches in recent years, significant efforts have been made on studying and engineering adeno-associated virus (AAV) capsid, in order to increase efficiency in targeting specific cell types that are non-permissive to wild type (wt) viruses and to improve efficacy in infecting only the cell type of interest (Abstract). Moreover, Hybrid serotypes of AAV have been shown to have tremendous potential for efficient gene delivery and for understanding AAV biology in the past (p. 307, 2nd column).
It would have been obvious to one of ordinary skill in the art at the time of the effective filing date to substitute the AAV9 capsid of the vector taught by Zhang to a hybrid capsid serotype of AAV9.rh as taught by Duan and Choi with a reasonable expectation of success. An artisan would be motivated to do so, as Duan and Choi demonstrate that AAV9 and AAVrh74 serotypes are both utilized to treat Duchene muscular dystrophy and Choi provides motivation to combine the two into a hybrid AAV in order to improve efficacy in infecting only one cell type.
Therefore, the invention would have been obvious to one of ordinary skill in the art at the time of the effective filing date
Conclusion
No claims are allowed.
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/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/MARIA G LEAVITT/Supervisory Patent Examiner, Art Unit 1634