DETAILED ACTION
Claim Status
As of the Non-Final Office Action mailed 2/9/2026, claims 9, 11-15, and 23-24 were pending.
In Applicant's Response filed on 8/10/2026, claims 9 and 11-14 were amended, claims 23-24 were canceled, and claim 25 was newly added.
As such, claims 9, 11-15, and 25 are pending and have been examined herein.
Withdrawn Objections/Rejections
The objections and rejections presented herein represent the full set of objections and rejections currently pending in this application. Any objections or rejections not specifically reiterated are hereby withdrawn.
The rejection of record of claims 9 and 11-15 under 35 USC § 112(b) have been withdrawn in view of Applicant’s amendment to claim 9 and 14. The rejection of claim 23-24 is moot in view of their cancelation.
The rejection of record of claims 9 and 11-15 under 35 USC § 112(a) for inadequate written description have been withdrawn in view of Applicant’s amendment to claim 9 and 14. The rejection of claim 23-24 is moot in view of its cancelation.
The rejection of record of claims 9 and 11-15 under 35 USC § 112(a) for lack of enablement have been withdrawn in view of Applicant’s amendment to claim 9 and 14. The rejection of claim 23-24 is moot in view of its cancelation.
The rejection of record of claims 23-24 under 35 USC § 103 as being unpatentable over Patel and Inouye as applied to claims 9, 11-12, and 14 and further in view of Gandjbakhch et al (Heart, May 2011; 97(10):844-9. Epub 3 Mar 2011) is moot in view of the cancelation of claims 23-24.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 9, 11-12, and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al (WO2017083750A1; of record) in view of Deangelis et al (WO2009126894A2, 4/10/2009; published 10/15/2009) and Inouye et al (Protein Expr Purif. 7 Feb 2015; 109:47-54; of record).
Regarding claim 9 in-part and 14 in-part, Patel teaches compositions for expression of biologically active peptides from a single vector for treatment of cardiac conditions (title).
Patel continues to teach a polypeptide can be incorporated in a polynucleotide sequence and can be introduced as a gene therapy (para 186). The genes and polypeptides that can be introduced to a subject with cardiomyopathy includes PKP2 (same para). The vector comprising the polynucleotide can be introduced in a cell and the cardiovascular disease can be ARVC (para 211-212). Any vector system can be used including adenovirus vectors (para 112). The expression vectors can contain suitable cardiac promoters (para 77).
Regarding claim 11 and 12, Patel teaches that AAV9 gene therapy evaluated in a pig model demonstrated protection from hemodynamic deterioration, improvement of cardiac function, and heart rate normalization (para 14). The polynucleotide can be in a pharmaceutical composition in a pharmaceutically acceptable excipient (para 24).
Patel does not teach:
the sequence encodes amino acid sequences of SEQ ID NO: 2 or SEQ ID NO: 4 (PKP2 isoforms a or b), or
the first sequence is codon-optimized,
Regarding i), Deangelis teaches methods and compositions for treatment of angiogenic disorders.
Deangelis continues to teach isoform 2a amino acid sequence of PKP2 (SEQ ID NO: 50), which is 100% identical to SEQ ID NO: 2 (see screenshot below).
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Deangelis also teaches the isoform 2b amino acid sequence of human PKP2 (SEQ ID NO: 51), which is 100% identical to SEQ ID NO: 4.
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Regarding ii), Inouye teaches genetic codes comprise 64 nucleotide triplets (codons) encoding 20 amino acids and 3 stop codons (see pg. 47, col 1, paragraph 1). The frequencies of codon usage among organisms differ markedly and at present, codon optimization of heterologous protein genes has been applied to achieve optimum expression of proteins in specific host cells such as bacteria, fungi, yeasts, plants, and mammals (see pg. 47, col 1, paragraph 1). The codon optimized genes for proteins can be chemically synthesized using the suitable codons for the host cells without altering the amino acid sequences (see pg. 47, col 1, paragraph 1). Codon optimization for proteins has been proposed using several software applications and to express a heterologous protein in mammalian cells, the overall proportions of usage of each codon were altered to closely match human codon usage (see pg. 47, col 1, paragraph 1). This shows that codon optimization of a protein can be performed to achieve optimum expression in a host.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to modify the PKP2 vector as taught by Patel to produce either the 2a or 2b isoform of PKP2 as taught by Deangelis, to arrive at the instantly claimed invention. One of ordinary skill would have been motivated to make the modification with a reasonable expectation of success because Deangelis explicitly teaches known sequences of PKP2 isoforms capable of being used successfully for gene therapy as taught by Patel.
It also would have been obvious prior to the effective filing date of the instantly claimed invention to create a vector containing PKP2 and a cardiac specific promoter as taught by Patel and Deangelis, where the nucleotide sequence for PKP2 is codon optimized as taught by Inouye, to arrive at the instantly claimed invention. One of ordinary skill would have been motivated to modify the protein with a reasonable expectation of success because Inouye teaches that codon optimization of heterologous protein genes can be used advantageously to create coding sequences can be applied to achieve optimum expression of proteins in specific host cells, such as in mammalian cells. Furthermore, codon optimization for protein expression in selected cells has been routine since at least 2015 (see date of Inouye reference). Multiple tools, including various software programs (such as the one utilized by Inouye), had been designed and were available to researchers for generating codon-optimized sequences for any gene based on knowledge of highly expressed genes in the host of interest. Thus, one of ordinary skill would have found it obvious to optimize the codons of proteins because Inouye suggests optimization via selection of preferred codons for use in a specific host cell of interest. Therefore, it would have been obvious to one of ordinary skill at the time of filing to codon optimize the coding sequence of Patel and Deangelis in combination and arrive at instantly claimed codon optimized variant of the therapeutic protein.
Response to Arguments
Applicant’s arguments has been fully considered but they are not persuasive. Applicant’s arguments will be addressed following maintained rejections.
On p. 4-6 of Remarks, Applicant argues that Patel does not teach a PKP2 construct, sequence and discusses merely ARVC as one of four cardiomyopathies. Applicant further argues that neither Patel nor Inouye disclose a codon-optimized nucleic acid sequence that encodes SEQ ID NO: 2 or 4. Applicant further argues that Patel purportedly disparages the use of viral vectors, that modifying Patel would change the principle operation of the expression of S100A1, SDF-1alpha, and VEGF.
While Applicant’s arguments have been fully considered, they are not persuasive. First, Patel explicitly teaches “Multigenic expression of genes and proteins of interest can be mediated by a vector. Any vector system can be used including, but not limited to, plasmid vectors, retroviral vectors, lentiviral vectors, adenovirus vectors, poxvirus vectors, herpesvirus vectors, adeno-associated virus vectors, etc” (para 112 of Patel). While Patel does state that “Plasmid vectors are advantageous in avoiding host anti-viral immune responses” (same para), the disclosure of desirable alternatives does not necessarily negate a suggestion for modifying the prior art to arrive at the claimed invention (MPEP 2143.01(I)). “The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In In re Fulton, 391 F.3d 1195, 73 USPQ2d 1141 (Fed. Cir. 2004).
Moreover, Patel states “a polypeptide can be incorporated in a polynucleotide sequence described herein and introduced to a subject with a disorder, or in need of improved vasculogenesis. For example, a subject can have a cardiomyopathy disorder and can be treated by administration of a polynucleotide described herein to treat the disorder. In some cases, a polynucleotide encoding a gene or a polypeptide described herein can be introduced by gene therapy. Genes and polypeptides that can be introduced to a subject with a cardiomyopathy can include for instance: . . . , Plakophilin 2 (PKP2)” (para 186 of Patel). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including non-preferred embodiments. Merck & Co. v. Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005) (MPEP 2123(I)). Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). Deangelis shows that SEQ ID NO: 2 and 4 are known amino acid sequences of the 2a and 2b isoforms of PKP2 and Inouye provides sufficient teachings, suggestions, and motivations for codon optimization of sequences. Thus, Applicant’s arguments are not persuasive.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel, Inouye, and Deangelis as applied to claims 9, 11-12, and 14 above, and further in view of Carrier et al (US20160108430A1, 4/17/2014; published 4/21/2016; in IDS filed 4/12/2022).
The teachings of Patel, Deangelis, and Inouye in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 9 of which claim 13 depends. The teachings will not be repeated here.
Neither Patel, Deangelis, nor Inouye teach:
the cardiac specific promoter is TNNT2.
Regarding i), Carrier teaches a gene therapy vector for expressing an exogenous nucleic acid sequence comprising a nucleic acid sequence encoding a functional cardiac sarcomeric protein and a cardiomyocyte-specific promoter which is operably linked to the said nucleic acid sequence (see claim 1 of Carrier). Cardiac-specific promoter suitable for being used in the vector of the invention has an activity in cardiac cells which is at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, or at least 50-fold higher compared to its activity in a non-cardiac cell type (para 42).
Regarding claim 13, Carrier teaches that the cardiomyocyte specific promoter is human cardiac troponin T promoter (hTNNT2) (see claim 3 of Carrier).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a vector containing codon-optimized PKP2 and a cardiac specific promoter as taught by Patel, Deangelis, and Inouye in combination, where the cardiac promoter is TNNT2 as taught by Carrier, to arrive at the instantly claimed invention. Carrier shows that hTNNT2 can successfully be used in a gene therapy vector to express functional cardiac sarcomeric proteins. One of ordinary skill would have been motivated to simply substitute one known element [cardiac promoter of Patel, Deangelis, and Inouye in combination] for another [hTNNT2 promoter of Carrier] to obtain the predictable result of advantageously having a promoter that has at least 5-fold activity in cardiac cells as taught by the prior art.
Claim(s) 15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al, Deangelis et al, and Inouye et al as applied to claims 9, 11-12, and 14 above, and further in view of Kirn et al (WO 2019/060454 A3, Publication date March 28, 2019; previously cited).
The teachings of Patel, Deangelis, and Inouye in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 14 of which claim 15 depends. The teachings will not be repeated here.
Neither of these references teach an additional viral vector comprising a nucleic acid sequence encoding for one or more nonPKP2 sarcomeric proteins or functional variants thereof.
Kirn teaches AAV capsid protein variants that confer increased infectivity of one or more types of muscle cells as compared to the infectivity of the muscle cells by an AAV virion comprising the unmodified parental AAV capsid protein. Methods of using these rAAV capsid proteins and virions in research and in clinical practice, for example, in the delivery of nucleic acid sequences to one or more muscle cells for the treatment of muscle disorders and diseases (e.g., Abstract). Gene products delivered by the subject AAV variants can be sued to alter the level of gene products or gene product activity directly or indirectly linked to muscle diseases and trauma. Skeletal, cardiac or smooth muscle transduced with subject AAV variants can also be used as a biofactory or produce and secrete therapeutic proteins for the treatment of diseases in trans in distant organs. Genes whose gene products are directly or indirectly linked to genetic diseases include titin (TTN) (e.g., [0158], p. 72), troponin 1, troponin T2 (TNNT2), troponin C (TNNC1) (e.g., [0158], p. 73), actin alpha1 (cardiac muscle, ACTC1), actin alpha2 (ACTC2) (e.g., [0158], p. 74), and plakophilin 2 (PKP2) (e.g., [0158], p. 75). Titin, troponin 1, troponin T2, troponin C, actin alpha 1 and actin alpha2 are all non-PKP2 sarcomeric proteins.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to prepare therapeutic formulation that further comprises one or more additional viral vectors each comprising a nucleic acid sequence encoding for one or more non-PKP2 sarcomeric proteins or functional variants thereof because Patel, Deangelis, and Inouye in combination teaches an AAV vector for stable cardiac expression of PKP2 protein and Kirn teaches methods of using rAAV capsid variant proteins and virions in research and in clinical practice, for example, in the delivery of nucleic acid sequences to one or more muscle cells for the treatment of muscle disorders and diseases including smooth muscle and cardiac diseases. The nucleic acid sequences encode gene products that include titin (TTN) (e.g., [0158], p. 72), troponin 1, troponin T2 (TNNT2), troponin C (TNNC1) (e.g., [0158], p. 73), actin alpha1 (cardiac muscle, ACTC1), actin alpha2 (ACTC2) (e.g., [0158], p. 74), and plakophilin 2 (PKP2) (e.g., [0158], p. 75). It would be obvious for one of ordinary skill in the art to prepare a therapeutic formulation comprising one or more additional rAAV vector comprising a nucleic acid sequence encoding Titin, troponin 1, troponin T2, troponin C, actin alpha 1 or actin alpha2, in addition to the AAV vector expressing PKP2 protein, in order to deliver PKP2 gene and one or more sarcomeric protein gene to a subject for treating various skeletal and cardiac diseases with reasonable expectation of success.
Allowable Subject Matter
Claim 25 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims. Claim 25 recites, inter alia, “wherein the codon-optimized sequence comprises SEQ ID NO: 3.” The closest prior art, Patel, teaches gene therapy vectors that can contain, for example, PKP2 to treat cardiac conditions (see above). Inouye provides teachings related to why one of ordinary skill in the art would codon-optimize a gene sequence to create coding sequences can be applied to achieve optimum expression of proteins in specific host cells, such as in mammalian cells (see above). However, SEQ ID NO: 3, which is required by instant claim 25, is free of the prior art.
Conclusion
No claim is allowed.
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 nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/G.R./Examiner, Art Unit 1632
/MARCIA S NOBLE/Primary Examiner, Art Unit 1632
