DETAILED ACTION
This action is in reply to papers filed 12/3/2025. Claims 1-11, 17, 21-22 and 34 are pending with claims 17 and 21-22 examined herein.
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 .
Examiner’s Note
All paragraph numbers throughout this office action, unless otherwise noted, are from the US PGPub of this application US20230047424A1, Published 2/16/2023.
Withdrawn Rejection(s)
The 35 U.S.C. 103 rejection of claims 17-19, 21-24 as being unpatentable over Colella et al. (PgPub US20180327779A1, Published 11/15/2018), Heydari et al. (Zahedan Journal of Research in Medical Sciences 15.10 (2013)), Auricchio et al. (PgPub US20160076054A1, Published ) and Boye et al. (PgPub US20140256802A1, Published 9/11/2014) is withdrawn in view of amendments made to independent claim 17.
Maintained Rejection(s)
The 112 (a) lack of enablement rejection of claims 17-19 and 21-24 is maintained. Applicant’s arguments will be addressed following maintained rejection.
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 17 and 21-22 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. Although independent claim 17 has been amended, said amendments do not overcome the lack of enablement rejection. The previous rejection is copied below for Applicant’s convenience.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that “Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue.’ Not ‘experimentation;” (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
• (A) The breadth of the claims;
• (B) The nature of the invention;
• (C) The state of the prior art;
• (D) The level of one of ordinary skill;
• (E) The level of predictability in the art;
• (F) The amount of direction provided by the inventor;
• (G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure
Furthermore, the USPTO does not have laboratory facilities to test if an invention will 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. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
The Nature of the Invention: The inventive concept in the instant application is a gene therapy drug comprising a first vector comprising a first portion of a polynucleotide sequence encoding for a therapeutic protein; and a second vector comprising a second portion of the polynucleotide sequence encoding for the therapeutic protein, wherein the therapeutic protein is MYH7 of a functional variant thereof.
Amount of Direction Provided by Inventor/Working Examples: The specification discloses three examples. In ‘Example 1’, the transgene is split into two AAV vectors sharing homologous overlapping sequences, such that the reconstitution of MYH7 relies on homologous recombination. The specification teaches that in these example constructs, as illustrated in FIGS. 1A-1D, the size between the two ITR sequences is 4712 bases for the first AAV vector (FIG. 1B) and 4351 bases for the second AAV vector (FIG. 1C). The length of the overlap is 1055 bases (FIG. 1D). In ‘Example 2’, protein splicing occurs based on encoded intein sequences. In these example constructs, as illustrated in FIGS. 2A-2C, the first AAV vector encodes the first N-terminal 946 amino acids (FIG. 2B, not to scale) and the second AAV vector encodes the C-terminal amino acids 947-1935 (FIG. 2C, not to scale), though it is contemplated that other combinations of sequence ranges are possible. The size between the two ITR sequences is 4923 bases for the first AAV vector (FIG. 2B, SEQ ID NO: 8) and 4819 bases for the second AAV vector (FIG. 2C, SEQ ID NO: 9). MYH7 expression is under the control of the TNNT2 promoter. Flag, ZeoR, and Blasticidin are used to select the transduced cells. In ‘Example 3’, a highly recombinogenic exogenous sequence is used to trigger the homologous recombination. This sequence is spliced out after transcription because it will be recognized as an intron in the pre-mRNA. This sequence was placed between exons 20 and 21, though other possible insertion locations may exist and are contemplated. In these example constructs, as illustrated in FIG. 3 , the first AAV vector (SEQ ID NO: 10) contains the TNNT2 promoter driving the transcription of the first 20 exons of MYH7. An optimized sequenced is generally used to improve protein translation in the other examples, but in this example sequences of exons 20 and 21 are not optimized. Exon 20 is followed by the first 40 bases of endogenous intron 20, followed by the first 272 bases of the SEAP gene. The selection gene, chimeric intron, and flag are also present to improve transcription/translation efficacy and imaging. The second AAV vector (SEQ ID NO: 11) starts with the same 272 bases from the SEAP (for HR), followed by the last 40 bases of endogenous intron 20 and the whole non-optimized exon 21 of MYH7, followed by the sequence coding optimized exons 22-40 of MYH7.
There are several issues to note. First, Applicant claims the gene therapy drug prevents cardiomyopathy. "Prevention" is understood in the art to encompass total protection from disease or injury. Thus, given the high level of required effect, a high level of evidence showing prevention is also required. Examiner notes that one skilled in the art could not use the claimed drug to achieve the results of prevention of cardiomyopathy, as claimed, because the specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent cardiomyopathy. Reasonable guidance with respect to preventing cardiomyopathy relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to cardiomyopathy or have had cardiomyopathy. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of the onset of cardiomyopathy and link those results with subsequent histological confirmation of the presence of cardiomyopathy. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Such is not provided in the instant specification.
Second, all examples provide appear to be prophetic examples. For example, in ‘Example 3’, the specifications states that “[T]his sequence is spliced out after transcription because it will be recognized as an intron..” (Examiner’s emphasis). Moreover, no example is drawn to the use of the claimed product (~ gene therapy drug) to achieve a therapeutic benefit. This is problematic as Applicant is claiming the gene therapy drug treats or prevents cardiomyopathy.
The State of the Prior Art: Cannata et al. (Circ Res. 2020 May 8;126(10):1394-1414.) teach that as far as hypertrophic cardiomyopathy (HCM) is concerned, >1400 different pathogenic mutations in sarcomeric proteins have been related to the development of this condition, 80% of which are in the MYH7 and MYBPC3 genes. Here, in only a few cases, standard gene therapy was shown possible in animal models, for example, by overexpressing the normal MYBPC3 gene or a phosphomimetic variant of the myosin regulatory light chain—the MYL2 protein (Pg. 1408, Col. 2, para. 2). On background, Sweat et al. (Cardiovasc Aging 2023;3:28.) teach dominant pathogenic variants (PVs) in myosin heavy chain 7 (MYH7), the major myosin isoform in human ventricles, cause approximately 30% of HCM (Pg. 1). Sweat teaches use of base editing to target PVs have advanced the field by demonstrating that highly efficient and precise base editing can be achieved in vivo in postnatal cardiomyocytes and deployed to treat inherited heart conditions caused by dominant missense mutations. Sweat teaches this strategy will be applicable to conditions caused by C↔T or G↔A single nucleotide variants within sequences amenable to precise base editing. Compared to gene replacement by episomal AAV-mediated expression, genome editing may avoid cargo limitations that preclude the expression of large gene products. Gene editing can treat dominant PVs, such as MYH7R403Q, unlike gene replacement strategies more typically pursued in AAV gene therapy, which are better suited to correcting insufficient gene expression. Sweat adds that gene editing is also invulnerable to loss of AAV episomes, which may lead to waning efficacy of traditional AAV gene therapy over many years (Pg. 3, first paragraph).
The level of Predictability in the Art/Conclusion: The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. Due to the large quantity of experimentation necessary to establish vector mediated transfer of the wild type MYH7 gene or a functional variant thereof, the state of the art which establishes a lack of standard gene therapy studies in treating cardiomyopathy, the lack of guidance or evidence in the specification in treating or preventing cardiomyopathy with the claimed drug, it would have required undue experimentation for one skilled in the art at the time of the invention to practice the claimed invention.
Applicant’s Arguments/Response to Arguments
Applicant argues: The specification provides comprehensive guidance through three detailed examples that demonstrate different reconstitution strategies.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. As noted above, no example is drawn to the claimed use of the claimed product (~ gene therapy drug) to achieve a therapeutic benefit. This is problematic as Applicant is claiming the gene therapy drug treats or prevents cardiomyopathy. Critically, the art, as evidenced by previously cited Sweat et al., teaches AAV mediated expression of a wild type gene may be insufficient to treat dominant pathogenic variants (PVs) in myosin heavy chain 7 (MYH7), PVs that are responsible for approximately 30% of hypertrophic cardiomyopathy. The lack of in vitro and/or in vivo experiments in the specification- as it relates to treating cardiomyopathy- further exacerbates the issue raised in Sweat.
Applicant argues: The specification provides specific technical parameters that would enable a person of ordinary skill in the art to practice the claimed invention.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Technical parameters that would enable one of ordinary skill in the art to practice the claimed invention, in full, without undue experimentation includes, but is not limited to, route of administering the vector, the AAV serotype, in vitro study with analysis showing a therapeutic benefit of administering the vector, in vivo study with analysis showing a therapeutic benefit of administering the vector. None of these have been provided. All that has been provided is a means of making the vector.
However, the intended use of the claimed gene therapy drug recited in the preamble gives “life and meaning” to the claim. Per MPEP 2111.02, "[A] claim preamble has the import that the claim as a whole suggests for it." Bell Communications Research, Inc. v. Vitalink Communications Corp., 55 F.3d 615, 620, 34 USPQ2d 1816, 1820 (Fed. Cir. 1995). "If the claim preamble, when read in the context of the entire claim, recites limitations of the claim, or, if the claim preamble is ‘necessary to give life, meaning, and vitality’ to the claim, then the claim preamble should be construed as if in the balance of the claim." Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165-66 (Fed. Cir. 1999). Note also that Applicant’s inclusion of the phrase “a human subject in need thereof” is addressed by the Courts (Examiner’s emphasis). Indeed, in considering the effect of the preamble in a claim directed to a method of treating or preventing pernicious anemia in humans by administering a certain vitamin preparation to "a human in need thereof," the court held that the claims’ recitation of a patient or a human "in need" gives life and meaning to the preamble’s statement of purpose.). Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951). Although the claimed invention is drawn to a product, the recitation of a human subject “in need thereof” further gives life and meaning to the claimed gene therapy drug.
Applicant argues: The specification further provides detailed background on AAV vector construction and delivery methods.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. As noted above, no example is drawn to the claimed use of the claimed product (~ gene therapy drug) to achieve a therapeutic benefit. This is problematic as Applicant is claiming the gene therapy drug treats or prevents cardiomyopathy. Applicant has not specifically addressed the issue of treatment and prevention.
Applicant argues: Contrary to the Office Action's assertion regarding prophetic examples, the three examples in the specification provide specific vector constructs, sequence information, promoter selections, and reconstitution mechanisms that would enable the person of ordinary skill in the art to practice the claimed invention.
In Response: Applicant’s arguments have been fully considered, but are not found persuasive. Examiner maintains that all examples provide appear to be prophetic examples as they recited expected results. For example, in ‘Example 3’, the specifications states that “[T]his sequence is spliced out after transcription because it will be recognized as an intron.” Examiner’s emphasis. Nevertheless, the critical issue here is that no example is drawn to the claimed product treating or preventing cardiomyopathy.
The prior art teaches general difficulty in obtaining an animal model of cardiomyopathy in which standard gene therapy was shown possible. Neither the specification nor Applicant’s arguments address this issue. Moreover, Applicant claims the gene therapy drug prevents cardiomyopathy. However, as previously set forth- the essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of the onset of cardiomyopathy and link those results with subsequent histological confirmation of the presence of cardiomyopathy. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. Such is not provided in the specification nor Applicant’s response.
Because Applicant’s arguments were not found persuasive, the rejection is maintained.
Authorization to Initiate Electronic Communications
The examiner may not initiate communications via electronic mail unless and until applicants authorize such communications in writing within the official record of the patent application. See M.P.E.P. § 502.03, part II. If not already provided, Applicants may wish to consider supplying such written authorization in response to this Office action, as negotiations toward allowability are more easily conducted via e-mail than by facsimile transmission (the PTO's default electronic-communication method). A sample authorization is available at § 502.03, part II.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632