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
1. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 02/24/2026 has been entered.
Claims 1-15, 17-22, 25, and 26 have been cancelled. Claim 16 has been amended.
Claims 16, 23, and 24 are pending and under examination.
Claim Objections
2. Claim 16 should be rewritten as follows:
A pharmaceutical composition formulated for treating osteoarthritis in a subject in need thereof, comprising a polyion complex,
wherein the polyion complex comprises a cationic polymer and mRNA,
wherein the cationic polymer comprises a cationic unnatural amino acid as a repeating unit and the cationic unnatural amino acid comprises a group represented by
-(NH-(CH2)2)p-NH2, wherein p is 3 or 4, as a side chain,
wherein the mRNA encodes Runt-related transcription factor 1 (Runx1),
wherein the polyion complex is capable of inducing a detectable expression of the protein encoded by the mRNA in articular cartilage for 96 hours or 192 hours and without toxicity, upon intraarticular administration to a mouse,
wherein the cationic polymer is a block copolymer with polyethylene glycol, wherein the cationic polymer is represented by Formula (I):
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wherein
R1 is polyethylene glycol, optionally linked to the cationic polymer block via a linker,
R2 is methylene or ethylene,
R3 is -(NH-(CH2)2)p-NH2 where p is 3 or 4,
R4 is hydrogen, a protecting group, a hydrophobic group, or a polymerizable group,
X is a cationic natural amino acid,
n is any integer from 2 to 5000,
n1 is any integer from 0 to 5000,
n3 is any integer from 0 to 5000,
n - n1 - n3 is an integer equal to or greater than 0, and
wherein, although the repeating units in Formula (I) are shown in the particular order for the purpose of description, the repeating units may be present in any order; the repeating units may be present at random; and the repeating units may be same or different, and
wherein
(i) the pharmaceutical composition induces expression of Sox 9, type II collagen, and/or proliferating cell nuclear antigen (PCNA) in articular cartilage cells;
(ii) the pharmaceutical composition promotes early chondrogenic differentiation;
(iii) the pharmaceutical composition inhibits interleukin-1β (IL-1β) expression wherein the pharmaceutical composition is formulated for intraarticular administration,
and/or
(iv) the pharmaceutical composition inhibits osteophyte formation in the subject,
wherein the pharmaceutical composition is formulated for intraarticular administration.
3. Claims 23 and 24 are objected to because of the recitation “A pharmaceutical” in the preamble. Correction to “The pharmaceutical” is required.
Maintained Rejections
Double Patenting
4. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
5. Claims 16, 23, and 24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3 of U.S. Patent No. 10,232,054, in view of both Uchida et al. (Uchida et al. (PLOS ONE, 2013, 8: 1-8) and Yano et al. (Ann. Rheum., 2013, 72: 748-753), as evidenced by Liu et al. (Heliyon, 2023, 8: 1-9).
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets encompass the same polyion complex comprising an mRNA encoding a transcription factor. The patent specification discloses that “p” is 3 or 4, where p=3 enables high protein expression for 5 days (see column 6, lines 25 and 49-58).
The patent claim 1 discloses that R1 can be coupled to PEG to obtain a block copolymer. Furthermore, Uchida et al. teach that adding a PEG layer provides stability and enhanced mRNA expression (see Abstract; p. 2, column 1, second full paragraph and paragraph bridging columns 1 and 2). Thus, modifying the patent claims by further attaching a PEG chain to R1 would have been obvious to one of skill in the art to achieve the predictable result of obtaining a composition for enhanced mRNA delivery.
The patent claims do not recite that the transcription factor is Runx1. Yano et al. teach that Runx1 is downregulated in the osteoarthritic cartilage; Yano et al. teach that increasing the intraarticular Runx1 expression promotes early chondrogenic differentiation (instant claim 16) and repairs the degenerated cartilage (see Abstract; p. 748, paragraph bridging column 1 and 2; p. 751, column 1; paragraph bridging p. 751 and 752; p. 752, column 1; p. 753, column 1, first full paragraph). One of skill in the art would have found obvious to modify the patent claims by specifically using an mRNA encoding Runx1 and further formulate the resulting polyion complex for intraarticular administration to achieve the predictable result of obtaining a composition suitable to treat osteoarthritis, when treating osteoarthritis was desired. As evidenced by Liu et al., the recitation of inhibition of osteophyte formation (instant claim 16) is an inherent property of Runx1 (see p. 4, column 1, first paragraph).
Thus, the patent claims and the instant claims are obvious variants.
New Rejections
Claim Rejections - 35 USC § 103
6. 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.
7. Claims 16, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Uchida et al. (J. Am. Chem. Soc., 2011, 133: 15524-15532; Ushida1) , in view of both Uchida et al. (PLOS ONE, 2013, 8: 1-8; Ushida2) and Yano et al. (Ann. Rheum. Dis., 2013, 72: 748-753), as evidenced by Liu et al. (Heliyon, 2023, 8: 1-9).
Ushida1 teaches a polyplex comprising PEG-PAsp(DET) or PEG-PAsp(TEP) and plasmid DNA, where the polyplex is suitable for efficient in vitro and in vivo DNA delivery. PEG-PAsp(DET) and PEG-PAsp(TEP) are set forth by the claimed Formula I and have the structures:
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146
340
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60
320
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(p is 2)
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(p is 4; claims 16 and 24).
(see p.15525, column 1 and Scheme 1; p. 15526, Fig. 3; p. 15528, column 2 and Fig. 5; p. 15531, column 2, last paragraph).
Uchida1 teaches plasmid DNA and not mRNA (claim 16). Ushida2 teaches that mRNA is a safer alternative to plasmid DNA with respect to gene therapy because there is no risk of random genome integration when using mRNA. Ushida2 teaches that PEG-PAsp(DET) is suitable for the in vivo mRNA delivery; the in vivo administration of a PEG-PAsp(DET)/luciferase-encoding mRNA polyplex resulted in detectable luciferase expression for more than 120 h; (see p. 2, column 1, third and fourth paragraphs and Fig. 1; paragraph bridging p. 3 and 4; p. 4, column 1, first paragraph; p. 5, column 2; p. 6, Fig. 5). Based on these teachings, one of skill in the art would have found obvious modify the polyplexes taught by Uchida1 by replacing the plasmid DNA with an mRNA, to achieve the predictable result of obtaining a composition providing safer gene therapy.
Uchida1 and Uchida2 do not teach an mRNA encoding Runx1 nor do they teach formulating the lipoplex for intraarticular administration (claim 16). However, one of skill in the art would have reasonably concluded that the polyplexes could be used for the delivery of any mRNA. Furthermore, Yano et al. teach that Runx1 is downregulated in the osteoarthritic cartilage; Yano et al. teach that increasing the intraarticular Runx1 expression repairs the degenerated cartilage and that Runx1 promotes early chondrogenic differentiation, induction of Sox9 expression (see Abstract; p. 748, paragraph bridging column 1 and 2; p. 751, column 1; paragraph bridging p. 751 and 752; p. 752, column 1; p. 753, column 1, first and second full paragraphs). One of skill in the art would have found obvious to modify the polyplex by specifically using an mRNA encoding Runx1 and further formulate the resultant polyplex for intraarticular administration, to achieve the predictable result of obtaining a composition suitable to treat osteoarthritis. By doing so, one of skill in the art would have obtained a polyplex comprising an mRNA and a cationic polymer set forth by the claimed Formula (I), where p is 4 (claim 16).
As evidenced by Liu et al., inhibition of osteophyte formation (claim 16) is an inherent property of Runx1 (see p. 4, column 1, first paragraph).
With respect to detectable expression for 96 or 192 h upon administration (claim 16), Ushida2 teaches that the in vivo administration of a PEG-PAsp(DET)/luciferase-encoding mRNA polyplex resulted in detectable luciferase expression for more than 120 h (see above). One of skill in the art would have reasonably expected the same for the PEG-PAsp(DET)/Runx1-encoding mRNA polyplex. Furthermore, Ushida1 teaches that, similar to PEG-PAsp(DET), PEG-PAsp(TEP) is a very effective gene delivery agent. Thus, one of skill in the art would have also expected PEG-PAsp(DET)/Runx-encoding mRNA polyplex to mediate the similar prolonged expression.
Thus, the claimed invention was prima facie obvious at the time of its effective filing date.
Response to Arguments
8. Double patenting
The arguments regarding the formulation for intraarticular administration are not found persuasive. Based on Yano, one of skill in the art would have known how to formulate the polyion complex for intraarticular administration. While the specification exemplifies injecting 20 µl of a solution of 150 µg/ml mRNA in HEPES buffer, pH 7.3, the claims are not limited by this exemplification. Any formulation is encompassed by the claims, as the claims do not require a specific formulation. Nor do the claims require a specific nanoparticle size. While Yano’s formulation does not comprise nanoparticles, one of skill in the art would have been able to determine the optimal nanoparticle size by just using routine experimentation.
Furthermore, the cited prior art provides the motivation to use a Runx1-encoding mRNA. While the applicant argues that the claimed effects on osteophyte, Sox9, collagen II, and IL-1β are intrinsic functional limitations of the specific claimed composition, it is noted that these effects are inherent properties of Runx1. Formulating the polyion complex for intraarticular administration has no effect on these inherent properties, nor does formulating for intraarticular administration changes the structure of the cationic polymer or mRNA.
The applicant argues that the patent claims do not recite Runx1.
However, the patent claims do not have to specifically disclose Runx1. The double patenting rejection is not based on the obviousness, not the anticipation rationale. The obviousness rationale uses an analysis similar to the one undertaken under 35 USC § 103 and can use references supporting the obviousness analysis for the double patenting rejection (see MPEP 804 II B 3). The patent claims recite the mRNA encodes a transcription factor and Yano provides the motivation to select Runx1 as the transcription factor encoded by the mRNA.
For these reasons, the following arguments are not found persuasive: (1) the patent claims do not address inhibiting osteophyte formation; (2) significant osteophyte inhibition was an unexpected therapeutic outcome (as evidenced by Liu, inhibiting osteophyte formation is an inherent property of Runx1); and (3) Liu is inapplicable to the NSDP context.
The argument that Liu does not demonstrate osteophyte formation via in vivo mRNA delivery is not found persuasive. Runx1 would exhibit the same activity regardless of how it is administered. Apart from an argument, the applicant did not provide any evidence indicating that administered Runx1 as an mRNA would change its inherent properties.
The argument that the patent specification only exemplifies PEG-PAsp(DET) is not found persuasive because the patent specification discloses that “p” could be 3 or 4, where p=3 provides expression for 5 days. MPEP 804 B 2(a) states:
In analyzing the disclosure of the reference patent or application, a determination is made as to whether a portion of the disclosure is directed to subject matter that is encompassed by the scope of a reference claim. For example, assume that the claim in a reference patent is directed to a genus of compounds, and the application being examined is directed to a species within the reference patent genus. If the reference patent includes a disclosure of several species within the scope of the reference genus claim, that portion of the disclosure should be analyzed to determine whether the reference patent claim, as properly construed in light of that disclosure, anticipates or renders obvious the claim in the application being examined. Because that portion of the disclosure of the reference patent is an embodiment of the reference patent claim, it may be helpful in determining obvious variations of the reference patent claim.
For these reasons, the arguments that (1) increased expression with PEG-PAsp(TET) was unexpected; and (2) the patent claims lack specificity and do not supply the motivation or expectation of success are not found persuasive. The rejection is not based on modifying the claims by replacing the cationic polymer recited in the patent claims with PEG-PAsp(TET) or PEG-PAsp(TEP). PEG-PAsp(TET) and PEG-PAsp(TEP) are two embodiments of the patent claims, which are specifically disclosed by the specification.
The argument of lack of reasonable expectation of success in delivering the mRNA to the cartilage is not found persuasive because the claims are composition, not method claims. And even assuming that the claims would be method claims, the argument would still not be found persuasive because it is not supported by any evidence.
9. No claim is allowed.
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/ILEANA POPA/Primary Examiner, Art Unit 1633