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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/01/2025 has been entered.
Claim Status
As of the Final Office Action mailed 6/30/2025, claims 9, 11-15, and 23-24 were pending.
In Applicant's Response filed on 12/01/2025, claims 9 and 14 were amended.
As such, claims 9, 11-15, and 23-24 are pending and have been examined herein.
Withdrawn Objections/Rejections
The rejection of record of claims 9, 11-14, and 23-24 under 35 USC § 103 as being unpatentable over Cruz et al. (Journal of American College of Cardiology, 2015; Vol. 64, No.14, p. 1438-1450, IDS; previously cited) in view of Inouye et al (Protein Expr Purif. 7 Feb 2015;109:47-54) have been withdrawn.
The rejection of record of claim 15 under 35 USC § 103 as being unpatentable over Cruz et al. (Journal of American College of Cardiology, 2015; Vol. 64, No.14, p. 1438-1450, IDS; previously cited) in view of Inouye et al (Protein Expr Purif. 7 Feb 2015;109:47-54) as applied to claims 9, 11-14, and 23-24 and further in view of Kirn et al. (WO 2019/060454 A3, Publication date March 28, 2019; previously cited) have been withdrawn.
New Grounds of Rejections
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 9, 11-15, and 23-24 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.
Claim 9 recites “a first codon-optimized sequence encoding for non-mutated plakophilin-2.” First, codon optimization is the introduction of synonymous mutations. Second, the recitation of “a functional variant thereof” necessarily includes functional mutants of PKP2. Thus, the claim is unclear.
Claim 14 recites “a first codon-optimized sequence encoding for non-mutated plakophilin-2.” First, codon optimization is the introduction of synonymous mutations. Second, the recitation of “a functional variant thereof” necessarily includes functional mutants of PKP2. Thus, the claim is unclear.
Generally, when the claims are indefinite, vague or unclear, they cannot be construed without speculation or conjecture; therefore, the indefinite claims are not treated on the merits with respect to prior art. See In re Steele, 305 F.2d 859, 862 (CCPA 1962) (A prior art rejection cannot be sustained if the hypothetical person of ordinary skill in the art would have to make speculative assumptions concerning the meaning of claim language.); see also In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970) ("If no reasonably definite meaning can be ascribed to certain terms in the claim, the subject matter does not become obvious-the claim becomes indefinite."). Notwithstanding Steele, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution.
Please note that claims 11-13 and 23-24 are included in this rejection for being dependent on indefinite claim 9. Please note that claim 15 is included in this rejection for being dependent on indefinite claim 14.
Claim Rejections - 35 USC § 112(a)
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.
Written Description
Claims 9, 11-15, and 23-24 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.
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 inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
Independent claim 9 (and thus 11-13 and 23-24) is broadly drawn to gene therapy vector adapted for expressing a nucleic acid sequence within cardiomyocytes of a human subject for treating or preventing arrhythmogenic right ventricular cardiomyopathy (ARVC), the nucleic acid sequence comprising: a first codon-optimized sequence encoding for non-mutated plakophilin-2 (PKP2) or a functional variant thereof; ana second sequence comprising a cardiac-specific promoter. Independent claim 14 (and thus claim 15) is broadly drawn to therapeutic formulation for treating or preventing arrhythmogenic right ventricular cardiomyopathy (ARVC) in a human subject, the therapeutic formulation comprising: a pharmaceutically acceptable excipient or carrier; and a viral vector comprising a codon-optimized nucleic acid sequence encoding for non- mutated plakophilin-2 (PKP2) or a functional variant thereof. The specification defines “functional variant” to mean that that the variant of the protein is capable of, partially or completely, fulfilling the function of the naturally occurring corresponding protein. Functional variants of a protein may include, for example, proteins that differ from their naturally occurring counterparts by one or more amino acid substitutions, deletions or additions, including those at least 30% amino acid identity (para 36 of the instant specification; i.e., with ability to maintain some amorphous ability to function akin to the wildtype protein). The specification does not define the function of PKP2 nor the relevant structures needed to “function.” This is extremely problematic because the specification fails to support possession of all these PKP2 variants and does not provide the necessary structure-function relationship to establish what would constitute a functional variant.
In support of the claimed genera of PKP2 and functional variants thereof, the specification discloses PKP2 isoform 2a (normal) and PKP2 isoform 2b (normal and codon-optimized). The specification contains no data generated for the PKP2 isoforms provided and, even if it did, that data cannot be reasonably extrapolated and applied to support possession of the entire claimed genus of PKP2 functional variants because no one species, combination, or variant accounts for the variability amongst the claimed genus. As in Ariad, merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species. “A patent is not a hunting license. It is not a rewards for the search, but compensation for its successful conclusion.” Brenner v. Manson, 383 U.S. 519, 536 (1996).
The specification, then, is considered devoid of sufficiently detailed, relevant, identifying characteristics demonstrating that Applicant was in possession of the claimed genus of viral vectors containing codon optimized PKP2 or functional variants thereof, variants, or fragments, i.e., additional complete or partial structures, other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure, or some combination thereof demonstrating possession of the claimed genus. Therefore, claims 9, 11-15, and 23-24 are rejected under 35 U.S.C. 112(a) for lack of written description.
Scope of Enablement
Claims 9, 11-15, and 23-24 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabled for (1) a gene therapy vector adapted for expressing a nucleic acid sequence within cardiomyocytes of a human subject for “lessen[ing] the severity of” arrhythmogenic right ventricular cardiomyopathy, and (2) a therapeutic formulation for “lessen[ing] the severity of” arrhythmogenic right ventricular cardiomyopathy (ARVC) in a human subject, does not reasonably provide enablement for preventing arrhythmogenic right ventricular cardiomyopathy. 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/or use the invention commensurate in scope with these claims.
While determining whether a specification is enabling, one considered 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 requirement, 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 at 737, 8 USPQ2d 1400, 1404 (Fed. Cir.1988)).
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore, skepticism raised in the enablement rejection are those raised in the art by artisans of expertise.
Nature of the invention:
A gene therapy vector adapted for expressing a nucleic acid sequence within cardiomyocytes of a human subject for treating or preventing arrhythmogenic right ventricular cardiomyopathy (ARVC), the nucleic acid sequence comprising: a first codon-optimized sequence encoding for non-mutated plakophilin-2 (PKP2) or a functional variant thereof; and a second sequence comprising a cardiac-specific promoter. A therapeutic formulation for treating or preventing arrhythmogenic right ventricular cardiomyopathy (ARVC)in a human subject, the therapeutic formulation comprising: a pharmaceutically acceptable excipient or carrier; and a viral vector comprising a codon-optimized nucleic acid sequence encoding for non- mutated plakophilin-2 (PKP2) or a functional variant thereof.
The state of the prior art:
The state of the prior art for preventing arrhythmogenic right ventricular cardiomyopathy was unpredictable before the effective filing date of the claimed invention.
The breadth of the claims:
The claims encompass a gene therapy vector containing a codon-optimized sequence encoding for non-mutated plakophilin-2 (PKP2) or a functional variant thereof and a second sequence comprising a cardiac-specific promoter to treat or prevent arrhythmogenic right ventricular cardiomyopathy.
The specification defines “treating” to include the administration of a drug with the intent to lessen the severity of or prevent a condition, e.g., heart disease (para 24). As such, the breadth of the claims as it relates to “treating” ARVC encompasses preventing ARVC.
The level of skill in the art:
The level of skill is high that requires a researcher with a PhD degree.
The working examples and guidance provided:
The specification discloses an illustrative example in which a PKP2 isoform2a cDNA sequence is cloned under the cardiac-specific TNNT2 promoter and using AAV2 internal terminal repeats, a construct with Flag added on, and the PKP2 being either codon-optimized and the 2b isoform. The specification states that the AAV6-TNNT2-PKP2 is used to transfect iPSC-CMs in 2D cell cultures including: normal cardiomyocytes; cardiomyocytes carrying1 heterozygous PKP2 mutation (from ARVC patients); and cardiomyocytes carrying two PKP2 mutations in trans. The specification contemplates that transfection would correct PKP2 haploinsufficient or completely deficient cells.
The specification fails to provide any working examples in which a gene therapy vector containing PKP2 and a cardiac-specific promoter is used to prevent ARVC.
The unpredictable nature of the art:
The claims encompass a PKP2 gene therapy vector to treat or prevent ARVC. Preventing ARVC using gene therapy was unpredictable before the effective filing date of the claimed invention.
Prevention:
Johns Hopkins Medicine (“Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy”; Retrieved from the Internet 2/2/2026) states that arrhythmogenic right ventricular is a rare familial disorder that may cause ventricular tachycardia and sudden cardiac death in young, apparently healthy individuals (first para). The clinical hallmark of the disease is ventricular arrhythmias, arising predominantly from the right ventricle and the pathological hallmark of the disease is fibrofatty replacement of right ventricular myocardium (same para). It states that in some patients, the first sign of ARVD is sudden cardiac arrest (“What are symptoms of ARVD/C?”). It also states that there is no single test that can either establish or exclude ARVD/C. This shows that ARVC is a genetic condition that has no test to establish or exclude an ARVD diagnosis and, for some, the first sign of disease is cardiac arrest. Thus, one of ordinary skill would not understand ARVD/C to be preventable.
Vector gene therapy:
Kotterman et al. (2014 Nature Reviews, Vol. 15, p. 445-451) reports that AAV still has significant challenges regarding successful use in treatment regimens (pg. 450 col. 2). Specifically Kotterman points out widespread natural exposure to AAVs has resulted in a large portion of the population with neutralizing antibodies specific to capsids in the blood and other body fluids, which markedly limit gene delivery by many natural vectors... following cellular transduction, AAV capsid epitopes can become cross-presented on major histocompatibility complex (MHC) class I molecules, which leads to the elimination of transduced cells by capsid-specific cytotoxic T lymphocytes and the corresponding loss of gene expression. For systemically administered viruses, the liver is often the default destination, which can represent a barrier when other organs are the intended targets. In addition, endothelial cell layers, especially those within the blood-brain barrier, pose a physical barrier for entry into a tissue. A vector that gains access to an organ, or that is directly administered to that organ, can then encounter numerous transport barriers to efficient transduction of the often-large tissue volumes involved in disease, including cell bodies and intervening extracellular matrix to which many AAV variants bind. The surface of a target cell may lack the primary and/or secondary receptors that are necessary for vector binding and internalization. Furthermore, endosomal escape, proteasomal escape, nuclear entry and vector unpackaging all represent barriers to transduction" (e.g. p. 447, under BOX 1).
Shim et al. (2017, Current Gene Therapy, Vol. 17, No. 5, p. 1-18) reports that in all gene therapy applications, delivery issues are essential, and nucleic acids are highly polar macromolecules and cannot diffuse through cell membranes. For the delivery of nucleic acids into target cells, viral and nonviral methods have been used. Despite success, viral vectors still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems (e.g. p. 1, right column, 2nd paragraph). Although nonviral methods have many advantages, including safety, the reasons these methods are falling behind viral methods with regard to outcomes might still be a matter of “delivery”, including passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release. Behavior in the physiological environment is the most important hurdle for vectors (e.g. p. 13, left column, 4th full paragraph). Thus, viral vector delivery of nucleic acid still suffer from various challenges, including cytotoxicity, immune response, tumorigenicity, cargo capacity and production problems. Nonviral delivery of nucleic acid still face the hurdle of passing in vivo physiological barriers, cellular/nuclear uptake, and endosomal release.
Lenzi et al. (2014, NCBI Bookshelf, A Service of the National Library of Medicine, National Institute of Health, Oversight and Review of Clinical Gene Transfer Protocols: Assessing the Role of the Recombinant DNA Advisory Committee. Washington (DC): National Academies Press (US), pages 1-16) discuss scientific hurdles of gene transfer in vivo. Some scientific hurdles, such as the absence of efficient delivery systems, difficulty with sustained expression, insertional mutagenesis and host immune reactions, remain formidable challenges to the field of gene transfer. Many of the hurdles have to do with providing efficient gene delivery. For examples, the vector uptake and distribution must be tightly controlled so that expression of the vector-encoded gene remains within the therapeutic range-if the expression is too low, the functional protein product may not be produced at a high enough concentration to effectively restore the intended biochemical pathway. Transcription of the new genetic material must remain stable so that the transgene is expressed as long as necessary to treat the disease. The degree to which the vector containing the transgene is taken up in a sufficient number of target cells is influenced by vector size and stability, the extent of target tissue vasculature, and the efficiency of interactions between vector and host cell receptors. The ideal vector would be cell-type specific, but the design of either non-viral or viral vectors that successfully target a specific cellular receptor has been elusive despite a great deal of effort. To date, re-engineered viral vectors are often too large, too unstable, or otherwise unable to reach the nucleus of some cell types. Non-viral gene delivery remains prohibitively inefficient for most therapeutic applications (e.g. p. 10, under “Scientific Hurdles”). For viral vectors, especially adenoviral and adeno-associated viral vectors, the exposed individuals have circulating antibodies that can interfere with transduction of closely related recombinant vectors. The control of an unanticipated immune response can be complicated by the challenge of "turning off" expression of transgene driven by constitutive, non-conditioned promoter sequence specifically designed to always be "on" (e.g. p. 11, 1st paragraph).
In addition, post-dated art Bulcha et al. (2021, Signal Transduction and Targeted Therapy, 6:53, p. 1-24) discusses “Viral vector platforms within the gene therapy landscape” (e.g. Title). Bulcha reports the challenges of rAAV vector for gene therapy include immunogenicity towards the vector remains the largest challenge for AAV-based gene therapies. In fact, the immune system will always be a major barrier for any gene therapy approach. The adaptive immunity to the capsid and the foreign transgene represents major factors for decreased efficacies (e.g. p. 14, bridging left column and right column). “Mechanisms for innate immunity have been well-described in response to viruses, but exploration of innate immune response towards AAV vectors is understudied… In addition, evidence is accumulating for the possibility that the AAV vector genome can elicit an innate immune response, necessitating an area of research that is critically needed” (e.g. p. 14, right column, 2nd full paragraph). Finally, a challenge that must be confronted is managing the right treatment doses, which may be at the heart of the strong immunological responses and subsequent toxicities seen in recent trials… These studies and others indicate that further evaluation of the appropriate routes of administration, capsid choice, and vector genome designs are still needed, even for approved drugs (e.g. Bridging, p. 14, right column and p. 15, left column).
The degree to which the vector containing the nucleic acid sequence is taken up in a sufficient number of target cells is influenced by vector size and stability, extent of target tissue vasculature, and the efficiency of interactions between vectors and host cell receptors. The challenges of AAV vector for gene therapy including immunogenicity towards the vector remains the largest challenge for AAV-based gene therapies. Administration routes play an important role to determine whether sufficient vector can be obtained at target sites in a subject. Different administration routes of the nucleic acid can result in different efficiency of gene expression and can influence whether sufficient expressed gene product can be obtained at the target cells so as to perform its purpose in vivo.
The extremely broad scope of the claims and lack of guidance in the specification exacerbates a highly unpredictable art regarding using gene therapy to prevent ARVC. While the results presented in the art do not necessarily preclude Applicant’s hypothesis, they certainly fail to support it in its totality that any gene therapy vector can prevent ARVC on its own. Applicants do not provide the details of how the vector as broadly claimed could be used to prevent ARVC nor is there a reduction to practice the instant claims to prevent ARVC. Consequently, the prior and post-filing art, when combined with the lack of disclosed direct experimental test of Applicant’s hypothesis, shows that one of ordinary skill would have no basis to reasonably predict or conclude that the gene therapy as claimed could be used alone to preventing ARVC. It is noted that, though not controlling, the lack of working examples is a factor to be considered in a case involving both physiological activity and an underdeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, they run the risk that unless one of skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them (Ex parte Sudilosky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971)).
In essence, the specification merely presents an idea of, and leaves it entirely up to the practitioner to determine whether the claimed vector would produce a therapeutically relevant preventative effect in a subject having ARVC. It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor or exemplified in the specification, reasonable detail must be provided in order to enable one of ordinary skill to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph. Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to practice the claimed invention and would require undue experimentation to practice over the full scope of the invention claimed.
The amount of experimentation necessary:
One of ordinary skill in the art could not reasonably take the prophetic examples of the specification and readily or immediately apply instantly claimed gene therapy vector to prevent ARVC as embraced by the claims. These teachings do not reasonably support these gene therapy vectors as a potential preventative for ARVC. One of ordinary skill in the art before the effective filing date of the claimed invention would be required to trial and error identify and select a “subject” from the broad genus of potential subject populations (both those with and without ARVC or clinical symptoms), as well as from subpopulations of disease progression for treatment, preparation of various vectors for the expression of nucleic acids, administration of the various vectors to various subjects via various administration routes, trial and error experimentation to determine whether sufficient vectors reach the target sites in vivo, trial and error experimentation to determine whether sufficient PKP2 vector is expressed at the target site in vivo, and trial and error experimentation to determine whether therapeutic effect can be provided to ameliorate or prevent various pathological symptoms of ARVC in vivo.
For the reasons set forth above, one skilled in the art before the effective filing date of the claimed invention would not be able to make and/or use the invention as claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 9, 11-12, and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al (WO2017083750A1) in view of Inouye et al (Protein Expr Purif. 7 Feb 2015; 109:47-54; previously cited).
Please note that the preamble “for treating or preventing cardiomyopathy in a human subject” in claims 9 and 14 merely states the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitation. The preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02(II)).
Patel teaches compositions for expression of biologically active peptides from a single vector for treatment of cardiac conditions (title). The reference teaches , 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). 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). This reads on “gene therapy vector adapted for expressing a nucleic acid sequence within cardiomyocytes of a human subject for treating or preventing arrhythmogenic right ventricular cardiomyopathy (ARVC), the nucleic acid sequence comprising: a first . . . sequence encoding for non-mutated plakophilin-2 (PKP2); and a second sequence comprising a cardiac-specific promoter” as in instant claim 9, “wherein the gene therapy vector comprises a viral vector, and wherein the viral vector comprises an adeno-associated virus (AAV) comprising one or more of AAV9” as in instant claim 11; “wherein the viral vector comprises . . . AAV9” as in instant claim 12; and “therapeutic formulation for treating or preventing arrhythmogenic right ventricular cardiomyopathy (ARVC)in a human subject, the therapeutic formulation comprising: a pharmaceutically acceptable excipient or carrier; and a viral vector comprising a codon-optimized nucleic acid sequence encoding for non- mutated plakophilin-2 (PKP2) or a functional variant thereof” as in instant claim 14.
Patel differs from the instant invention in that it does not teach that the PKP2 is codon-optimized.
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 and reads on “a first codon-optimized sequence” as in instant claim 9 in part and “a viral vector comprising a codon-optimized nucleic acid sequence” as in instant claim 14 in part.
Therefore, it 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, 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 arrive at instantly claimed codon optimized variant of the therapeutic protein.
Response to Arguments
Applicant’s arguments regarding the previously cited Cruz reference have been considered but are moot because the new ground of rejection does not rely on this reference for any teaching or matter specifically challenged in the argument.
On p. 6 of Remarks, Applicant argues that Inouye does not suggest applying codon-optimization specifically to non-mutated PKP2 for ARVC therapy.
In response, the examiner notes that the Inouye reference does not need to specifically suggest applying codon optimization to Applicant’s instantly claimed PKP2 sequence. Rather, all the reference needs to do is provide one of ordinary skill in the art some teaching, suggestion, or motivation for why one would codon-optimize sequences generally, such that it would be applicable and routine to any sequence including PKP2. It flows logically that any benefits generally known about codon-optimization would apply to any nucleic acid, including Applicant’s PKP2, based on the knowledge gleaned from at least the Inouye reference. Thus, Applicant’s argument is not persuasive.
Claim(s) 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al in view of Inouye et al as applied to claims 9, 11-12, and 14 above, and further in view of Carrier et al (US 20160108430 A1, 4/17/2014; published 4/21/2016).
The teachings of Patel 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.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the cardiac specific promoter is TNNT2.
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). The reference 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 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 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 in view of 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 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.
The difference between the combined teachings and the invention as instantly claimed is that they do not 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 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.
Response to Arguments
Applicant has not provided any arguments challenging the specific teachings of cited reference Kirn nor has Applicant attempted to distinguish the instantly claimed invention from what is taught in the prior art reference.
Claim(s) 23-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al in view of Inouye et al as applied to claims 9, 11-12, and 14 above, and further in view of Gandjbakhch et al (Heart, 2011 May; 97(10):844-9. Epub 2011 Mar 3).
The teachings of Patel and Inouye in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 9 of which claims 23 and 24 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the PKP2 is isoform 2a (as in instant claim 23) or isoform 2b (as in instant claim 24).
Gandjbakhch teaches that arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart disease in which mutations affecting Plakophilin-2 (PKP2) are the most frequently detected (abstract). However, pathogenicity of variants is not always fully determined. PKP2 encodes two isoforms, the longest (PKP2b) includes the alternatively spliced exon 6, which is routinely screened for molecular diagnosis, despite the absence of data on cardiac expression of PKP2 isoforms (same para). Proximal restriction sites BstEII and XmnI were used to insert exon 6 in pPKP2a producing pPKP2b (Methods). The pPKP2a and pPKP2b vectors were transiently expressed in HEK293 cells (same para). The reference teaches that PKP2A was shown to be the major isoform expressed in human heart tissue (abstract). PKP2b, if it exists, is a very rare isoform in humans (In silico analysis, para 1). A Caucasian male who died suddenly at 16 years of age had an autopsy revealed ARVC. His variant mutation, located within the exon 6, was specific of PKP2B (Results para 1). This shows that PKP2 a and b isoforms are relevant for ARVC, even though 2b is rare.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create a gene therapy vector containing PKP2 as taught by Patel and Inouye in combination, where the PKP2 is the a or b isoform as taught by Gandjbakhch, to arrive at the instantly claimed invention. As Gandjbakhch shows the 2a isoform is the dominant isoform in ARVC, one of ordinary skill would have been motivated to use the 2a isoform in the vector of Patel and Inouye in combination with a reasonable expectation of advantageously being able to target the main mutation in most ARVC cases as taught by the prior art. One of ordinary skill would also have been motivated to use the 2b isoform to capture those with rarer mutations in PKP2 as taught by the prior art.
Conclusion
No claim is allowed.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632