DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s response to restriction requirement filed on July 9, 2025 have been received and entered. Claims 1-40 are pending in the instant application.
Election/Restrictions
Applicant’s election without traverse of claims 1-9, 18-26 (group I) in the reply filed on July 9, 2025 is acknowledged.
Claims 10-17, 27-40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on July 9, 2025.
Priority
This application is a 371 of PCT/US2020/050411 filed on 09/11/2020 that claims priority from US provisional application no 62/898,958 filed on 09/11/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 03/10/2022 and 10/12/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner.
Claims 1-9, 18-26 are under consideration.
Claim Objections
Claims 2-8, 19-25 are objected to because of minor inadvertent syntax error: In the instant case, recitation of “wherein said ratio consists of” should be replaced with –wherein said ratio is--. Or -- wherein said molecules of modRNAs are present in said composition in the ratio of --Appropriate correction is required.
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.
Claims 1-9 are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al (WO2016134293, dated 08/25/2016)/ Meis (US20140328825, dated 11/06/2014), Srivastava et al (WO2017/173137, 10/5/2017, Lu et al (PNAS, 2011, 15876-15880), Lopez (Mol. Cell Bio. 1992, 1674-1679) in view of Sultana et al (Molecular Therapy, 2017, 1306-1315) as evidenced by McGrath et al (J. Vis. Exp. (141), e58687, 1-13).
Claims are directed to a composition comprising molecules of modified mRNA (modRNA) encoding GATA Binding Protein 4 (G), modRNA encoding Myocyte Enhancer Factor 2C (M), modRNA encoding T-box 5 (T), modRNA encoding Heart- and neural crest derivatives- expressed protein 2 (H), modRNA encoding dominant negative transforming growth factor beta (dnT), and modRNA encoding dominant negative Wingless-related integration site 8 (dnW), wherein said molecules of modRNAs are present in said composition in a ratio of G:M:T:H:dnT:dnW. The claim recites the phrase comprising is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (see MPEP2111.03).
Claim interpretation: independent claims as such neither recite (i) how mRNA is modified nor does the composition requires (ii) any specific resulting outcome or (iii) modRNAs are present in said composition in any specific ratio.
With respect to claims 1, 9, Patel teaches a composition comprising a nucleic acid encoding one or more of cardiac cell reprogramming factor including (i) GATA, (ii) Mef2c, (iii)Tbx5 and (iv) Hand2, wherein the nucleic acid a modified mRNA molecule (abstract, para. 5-11, 14, 20 and claims 1-6 and 30). It is further disclosed that the composition further comprises a suitable carrier intended for administration into a mammal using any suitable route of administration, including injection into the heart (see 92). Likewise, Meis teaches a composition comprising mRNA encoding at least one TF selected from group consisting of GATA4, HAND2, TBX5 and MEF2C (see para. 102) that is used to introduce into human or mammalian fibroblasts to reprogram into cardiac fibroblast cells (see para. 102), wherein mRNA is modified (see para. 289).
Patel differs from claimed invention by not disclosing that the claimed composition further includes a modified mRNA encoding dominant negative transforming growth factor beta (dnTGFB, dnT) and modRNA encoding dominant negative Wingless-related integration site Sa (dnWnt8a, dnW) and wherein said molecules of modRNAs are present in said composition in a ratio of G:M:T:H:dnT:dnW.
Srivastava cures the deficiency by introducing to a non-cardiomyocyte an effective amount of a WNT inhibitor and/or a TGF-beta1 inhibitor and one or more reprogramming factors comprising Gata4, Mef2c and Tbx5, thereby generating an induced cardiomyocyte or a cardiomyocyte-like cell. The WNT inhibitor or a TGF-b inhibitor is a small molecule or an siRNA (see para. 10-19, 106). The combination of references differs from claimed invention by not disclosing modRNA encoding for dominant negative TGF b or for dominant negative Wnt8a.
Before the effective filing date on instant application, Lu teaches mRNA coding for DN-Wnt8a and overexpression of this abolishes the expression of Wnt8a (see fig. 2C and S2B), while Lopez teaches overexpression of dominant negative mutants of TGFb1 can abolish endogenous secretion of TGF-1 (see abstract). The combination of references differs from claimed invention by not optimizing the molar ratio of mod mRNA in the composition.
Sultana teaches optimization of modRNA composition, concentration, and mode of delivery to achieve maximal efficacy of gene transfer in cardiac cells and in murine myocardium (see page 1307, col. 1, para. 1). It is disclosed that modified mRNA (modRNA), produced by the replacement of uridine with pseudouridine, resulted in changes to the mRNA secondary structure that prevented innate immune system recognition and RNase degradation. In addition, the replacement nucleotide, pseudouridine, occurs naturally in the body, and it enhanced translation of the modRNA compared to the unmodified version (see page 1306, col. 2, para. 1) Sultana further teaches optimal dose of modRNA per microliter for heart delivery. It is disclosed that the dose-response ratio is kept when 50 or 100 mg (see page 1312, col. 1, last para. ). This is further evident from the teaching of McGrath who reported a composition comprising a modified mRNA encoding six preprogramming factors could be optimized to a specific molar ratio of 3:1:1:1:1:1 (see page 2, para. 5).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the composition of Patel/ Meis by further incorporating a WNT inhibitor and a TGF-beta1 inhibitor as disclosed by Srivastava, in order to reprogram fibroblast into cardiomyocytes like cells, as instantly claimed, with a reasonable expectation of success, before the effective filing date of instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be further motivated to use mod RNA encoding dnWnt8a and dnTGFbeta as Wnt inhibitor and TGF inhibitor because prior art teaches overexpression of dnWnt8a and dnTGFb1 abolishes the expression of Wnt8a and TGFb1, while Sultana provided explicitly provided motivation to use modified mRNA (modRNA) in order to prevent innate immune system recognition and RNase degradation and achieve maximal efficacy of gene transfer in cardiac cells and in murine myocardium (see Sultana) . Given that each of the six factors were routinely used in different combination for reprogramming the fibroblast into a cardiomyocyte-like cells, it would have been obvious choice for one of ordinary skill in the art to combine different modRNA encoding the reprogramming factor each of which is taught by the prior art to be useful for the same purpose in order to produce a new composition that is to be used for the very same purpose. In the instant case the idea of combining them flows logically from there having been taught in the prior art. Thus, it would have only required routine experimentation to modify the composition of Patel/ Meis to further include of a dnWnt8a and dnTGFb as WNT inhibitor and a TGF-beta1 inhibitor and further modify to optimize the molar ratio of each of the modRNA to improve the efficiency of reprogramming. Absent evidence of any unexpected and/or superior results, one of skill in the art would have been expected to have a reasonable expectation of success because prior art reported use of nucleic acid encoding one or more of reprogramming factor to improve reprogramming of fibroblast cells into cardiomyocytes as evident from Patel and Srivastava in view of Lu and Lopez. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claims 18-26 are rejected under 35 U.S.C. 103 as being unpatentable over Patel et al (WO2016134293, dated 08/25/2016)/ Meis (US20140328825, dated 11/06/2014), Srivastava et al (WO2017/173137, 10/5/2017), Lu et al (PNAS, 2011, 15876-15880) in view of Sultana eta l (Molecular Therapy, 2017, 1306-1315) , McGrath et al (J. Vis. Exp. (141), e58687, 1-13) and further in view of Strelow et al (J. Exp. Med., 2000, 601-611) as evidenced by Choe (Analytical Biochemistry, 2018, 573, 73-76).
The teaching of Patel/Meis, Srivastava, Lu, Sultana as evidenced by McGrath have been discussed above and relied in same manner here. The combination of references differs from claimed invention by not disclosing that the composition additionally comprises a modRNA encoding acid ceramidase (A).
Strelow et al. cure the deficiency by disclosing that acid ceramidase (AC) overexpression protects cells from elevated cell death and restricts cellular stress (see fig. 4, abstract).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art to combine the teachings of prior art to modify the composition of Patel/Meis by further incorporating a WNT inhibitor and a TGF-beta1 inhibitor as disclosed by Srivastava, in order to reprogram fibroblast into cardiomyocytes like cells, as instantly claimed, with a reasonable expectation of success, before the effective filing date of instant invention. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would be further motivated to use mod RNA encoding dnWnt8a and dnTGFbeta as Wnt inhibitor and TGF inhibitor because prior art teaches overexpression of dnWnt8a and dnTGFb1 abolishes the expression of Wnt8a and TGFb1, while Sultana provided explicitly provided motivation to use modified mRNA (modRNA) in order to prevent innate immune system recognition and RNase degradation and achieve maximal efficacy of gene transfer in cardiac cells and in murine myocardium (see Sultana). Additionally, it would be further obvious to include modRNA encoding acid ceramidase in the composition of combination of prior art in order to reduce cell death and cellular stress caused by use of multiple modRNA composition as evident from the teaching of Strelow in view of Choe. Given that each of the six factors were routinely used in different combination for reprogramming the fibroblast into a cardiomyocyte-like cells, it would have been obvious choice for one of ordinary skill in the art to combine different modRNA encoding the reprogramming factor each of which is taught by the prior art to be useful for the same purpose in order to produce a new composition that is to be used for the very same purpose. In the instant case the idea of combining them flows logically from there having been taught in the prior art. Thus, it would have only required routine experimentation to modify the composition of Patel/Meis to further include of a dnWnt8a and dnTGFb as WNT inhibitor and a TGF-beta1 inhibitor and further modify to optimize the molar ratio of each of the modRNA to improve the efficiency of reprogramming and further include modRNA encoding AC that is expected to reduce cell death and cellular stress. Absent evidence of any unexpected and/or superior results, one of skill in the art would have been expected to have a reasonable expectation of success because prior art reported use of nucleic acid encoding one or more of reprogramming factor to improve reprogramming of fibroblast cells into cardiomyocytes as evident from Patel and Srivastava in view of Lu and Lopez. It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness See the recent Board decision Ex parte Smith, --USPQ2d--, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925.pdf).
Claim Rejections - 35 USC § 112
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 1, 9, 18 and 26 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 1 and 18 are vague and indefinite as metes and bounds of the phrase “said molecules of modRNAs are present in said composition in a ratio of G:M:T:H:dnT:dnW” in absence of any specific recitation of a molar ratio of each molecule is unclear. The recitation merely implies that each of the mod RNA is present in the composition and therefore recitation of said modRNA in a ratio without any numerical value is unclear. The claims fail to convey how molar ratio of one molecule compares to another molecule within the composition. For the sake of compact prosecution, they are interpreted as modRNA being present in said composition. Claims 9 and 26 are included in the rejection because they directly depend from the rejected base claim. 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 1-9, 18 and 26 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 composition of claim 1 requires a specific combination of molecules of modified mRNA (modRNA) encoding GATA Binding Protein 4 (G), modRNA encoding Myocyte Enhancer Factor 2C (M), modRNA encoding T-box 5 (T), modRNA encoding Heart- and neural crest derivatives- expressed protein 2 (H), modRNA encoding dominant negative transforming growth factor beta (dnT), and modRNA encoding dominant negative Wingless-related integration site 8 (dnW), wherein said molecules of modRNAs are present in said composition in a ratio of G:M:T:H:dnT:dnW (claim 1), while the composition of claim 18 requires molecules of modified mRNA (modRNA) encoding GATA Binding Protein 4 (G), modRNA encoding Myocyte Enhancer Factor 2C (M), modRNA encoding T-box 5 (T), modRNA encoding Heart- and neural crest derivatives- expressed protein 2 (H), modRNA encoding acid ceramidase (A), modRNA encoding dominant negative transforming growth factor beta (dnT), and modRNA encoding dominant negative Wingless-related integration site 8 (dnW), wherein said molecules of modRNAs are present in said composition in a ratio of G:M:T:H:A:dnT:dnW.
The claims read on a composition comprising a specific combination of six or seven molecules of modified mRNA (modRNA), wherein said molecules of modRNAs are present in said composition in a ratio of G:M:T:H:A:dnT:dnW.
The description provided in the specification support for a composition comprising modRNA for all of G, M, T, H, A, dnT and dnW, which cocktail is termed as "7G" in a specific molar ratio as set forth in Table 4. The specification lacks support for a composition comprising modRNA for G, M, T, H, dnT and dnW as set forth in claim 1. The specification teaches combination of modRNA GMTH cocktail is only disclosed with small molecules (SMI) that inhibit TGFb and WNT pathways (S8431542 and XAV939, respectively) as disclosed for example (see para. 142) of the specification. The specification teaches cocktail further comprises modRNA DN-TGFb and modRNA DN-Wnt8a is only disclosed when the cocktail discloses modRNA G, M, T, H, dnT and dnW. also contains acid ceramidase (A). Furthermore, all experimental data disclosed in the application showing efficient cardiac reprogramming are obtained only when using the "7G" cocktail, i.e. modRNA for all of G, M, T, H, A, dnT and dnW, at the specified molar ratio (see table 4, para. 152 and example 6-7). Figure 11 of the specification explore the potential of different ratios of reprogramming gene modRNA (GMTH) in 7G modRNA cocktail in driving cardiac reprogramming. Figures 11C-11F show partial groups such as g, h, i, j "N.S" with no effect. It can be seen that different gene ratios have a significant impact on the resulting reprogramming. The state of art explicitly reported that stoichiometry of transcription factors and culture conditions are critical for cardiac reprogramming (see page 4, col. 1 of Kojima and Ieda, Cell. Mol. Life Sci. 2017, 74:2203–2215). Nagamatsu et al ( Journal of Biological Chemistry, 2012, 287, 36273-36282) teaches a combination of four reprogramming transcription factors (RTFs) do not always induce pluripotency in somatic cells. It is suggested that the relative ratio of the four RTFs need to optimized.
The claims thus constitute a genus of composition comprising modRNA for G, M, T, H, A, dnT , dnW (claim 1) and additionally A (claim 18), wherein said molecules of modRNAs are present in said composition in a ratio of G:M:T:H:A: dnT:dnW that reprogram fibroblast to produce cardiomyocytes. The guidance in the specification is limited 7G" cocktail, i.e. modRNA for all of G, M, T, H, A, dnT and dnW in a specific molar ratio as set forth in Table 4 that are capable of reprogramming cells to produce cardiomyocyte like cells, the disclosed ratio of modRNA do not constitute a substantial portion of the claimed genus. The claims encompass
different modification in mRNA having different physicochemical properties and physiological functions at different ratio with the limited description as set forth in example 6-7 of the specification, and not any structural modRNA molecule combination, in any other ratio. There is expected to be uncertainties in the relationship of action between different molecules at different ratios. It may be obvious from various parts of the specification to make the instantly claimed combination. However, what makes “obvious” or what “might” be possible does not comply with the written description requirement to reasonably convey that the inventors had possession of the claims as now claimed. It is emphasized that the description must be sufficiently clear that persons of skill in the art will recognize that the applicant made the invention having those limitations. In re Wertheim, 541 F.2d 257, 262, 191 USPQ 90, 96 (CCPA 1976). Note that the written description requirement inquiry is “not a question of whether one skilled in the art might be able to construct the patentee’s device [invention] from the teachings of the disclosure....Rather, it is a question whether the application necessarily discloses that particular device.” (original emphasis). Martin v. Mayer, 823 F.2d 500, 504, 3 USPQ2d 1333, 1337 (Fed. Cir. 1987).
“One shows that one is “in possession’ of the invention by describing the invention, with all its claim limitations, not that which makes it obvious.” (original emphasis). Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 41 USPQ2d 1961 (Fed. Cir. 1997).
Accordingly, claims 1-9, 18 and 26 introduce matter that is not adequately described by the instant specification. Applicant is advised to point out a specific disclosure in the specification for a composition comprising modRNA for G, M, T, H, dnT , dnW (claim 1), wherein said molecules of modRNAs are present in said composition in any ratio of G:M:T:H:A:dnT:dnW, as claimed. Accordingly, the instant specification fails to reasonably convey that the applicants completed and had possession of the composition of the invention before the effective filing date of instant application.
Conclusion
No claims allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Ifkovits et al (PLoS One 2014, 9, e89678, 1-11) teaches TGFb inhibitor, SB431542 (SB), was identified as a small molecule capable of increasing the conversion of both mouse embryonic fibroblasts and adult cardiac fibroblasts to iCMs up to 5-fold (abstract).
Hadas (Circulation, 2020, 141, 11, 916-930) teaches enhancing AC activity reduced cell death under hypoxia conditions in vitro or during MI in vivo.
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/ANOOP K SINGH/ Primary Examiner, Art Unit 1632