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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The effective filing date of the instant application is 11/10/22 and not an earlier date (e.g., 11/11/21) because the applicant didn’t file an English translation of any of the foreign priority applications in a non-English language, including the earliest filed application on 11/11/21.
None of the foreign applications have an English translation. If the Applicant is interested to perfect priority to an earlier filed non-English language foreign application, an English language translation of the non-English language foreign application is required. The translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Claim Objections
Claim 1 is objected to because of the following informalities: the term “angiotensin-converting enzyme II” for the abbreviation ACE2 should be inserted in claim 1 for the skilled artisan to understand what the abbreviation stands for. Further it would be helpful to clarify the claim by explaining what the components of claimed composition nCoVshRNA-2ACE2 are.
Claim 27 is objected to because of the following informalities: the last line should be corrected for proper grammar to “…and an amino acid sequence of ACE2 polypeptide is codon-optimized”.
Claim 28 disclose that the ACE2 polypeptide is connected to the 3’ terminus of the antisense strand and terminus 5’ or 3’ of sense strand of the shRNA. However, a shRNA only has a 5’ and a 3’ terminus because it is a self-complementary structure with a spacer (loop region) connecting the two strands. See Figure 2.
Claim 29 is objected to because of the following informalities: recitations “shRNA3”, “shRNA5” and “shRNA7” involve specific sequences, therefore it is required to include sequence identifications (SEQ ID NOs) after them. Recitations “ch1” and “lip” are not defined what they stand for. Further claim 29 needs to be corrected for clarity by inserting recitation “wherein” in the fifth line to clarify claimed compositions: “…wherein the ACE2-siRNA/ACE2-shRNA comprises 2ACE2-shRNA3, 2ACE2-shRNA5, 2ACE2-shRNA8, and ACE2-siRNA;…”
Appropriate correction is required.
Improper Markush rejection
Claims 17-25 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of SEQ ID NOs in claims 17-25 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the sequences target different coronavirus gene. For example, SEQ ID NOs: 20-22 target ORF1ab gene and SEQ ID NOs: 30-32 target coronavirus S gene. SEQ ID NOs: 20-29 target ORF1ab gene (see Table 1). However, a sequence search for SEQ ID NO: 20 against publicly available databases does not result in a hit for SEQ ID NOs: 21 nor 22 and vice versa.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 26 and 28 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 26 recites “…ACE2 or a polypeptide thereof …” in the third line. It is not clear what polypeptide is related to, because ACE2 is a polypeptide itself. It is suggested to remove “a polypeptide” from the claim.
Claim 28 recites the limitation "the RBD" in the eighth line. There is insufficient antecedent basis for this limitation in the claim. Further, the whole recitation “…the ligating or the synthesizing comprises ligating the ACE2 or the RBD or ligating a polypeptide of the two separately on the sense strand and the antisense strand of the shRNA” has no clear meaning.
Claim 29 recites complexes comprising “ch1” and “lip”. Those recitations are not defined in the disclosure, therefore their meaning is unclear. For the purpose of examination it is assumed that “ch1” means DOTAP/Cholesterol comprising liposome as in specification paragraph [0083], but appropriate correction is required.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14-16 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 14-16 depend on claims 1, 12, 13, respectively, while claims 12 and 13 originally depend on claim 1 as well. Claims 14-16 add identical lengthy new limitations to the claims, essentially specifying that the targeting vector of claim 1 is ACE2 and further providing functional limitations describing mechanism of claimed composition activity. It is noted that preamble of claim 1 recites claimed composition as nCoVshRNA-2ACE2, further describing ligating targeting vector to shRNA, therefore from the name of composition it is clear that ACE2 plays a role of targeting vector. The same is confirmed in paragraph [0006] of instant specification. Therefore, limitations of claims 14-16 just reconfirm that targeting vector is ACE2, but do not further limit claims 1, 12, 13.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 11-26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN 113355288, September 2021, cited from machine translation) and in further view of Ebben et al (WO 2023/023597, claiming priority to 63/234478, filed August 2021) and Leavitt et al (US 2009/0123501, May 2009).
Li et al teach T-cell modified to express ACE2 capable of binding to SARS-CoV-2 for treatment of COVID-19 (see Abstract). Such T-cell can further comprise coding gene for shRNA targeting SARS-CoV-2, which can be expressed (see page 6). The shRNA aims to destroy SARS-CoV-2 genome in a cell targeted by ACE2 (see page 10).
Li et al do not teach conjugation of two ACE2 proteins to both ends of shRNA and encapsulating it in a liposome, or length of siRNA strands of 21-25 nucleotides, or siRNA of SEQ ID NO: 21.
Ebben et al teach virus-like particles comprising siRNAs and shRNAs targeting SARS-CoV-2, such siRNA or shRNA delivered by liposome (see paragraphs [0014-0017]). One of such siRNAs is of SEQ ID NO: 12 (see Table 1), 21 nucleotides long, and fully identical to instant SEQ ID NO: 21. shRNA is formed by connecting two complementary strands of siRNA at one end by a loop of 2-10 nucleotides (see paragraph [0073]).
Leavitt et al teach shRNA-protein conjugates (see paragraph [0151]).
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to conjugate shRNA taught by Ebben et al to ACE2 protein taught by Li et al as taught by Leavitt et al and encapsulate such conjugate in a liposome as taught by Ebben et al, arriving at instant invention. One of the ordinary skill in the art would be motivated to do so because Li et al teach a cell expressing two compounds targeting SARS-CoV-2: ACE2 protein capable of binding to the virus and siRNA capable of destroying viral genome, therefore treating the viral infection, motivating one of the art to combine both elements taught by Li et al in one conjugate by attaching ACE2 proteins to both ends of shRNA so that ACE2 protein targets the siRNA to viral particle, because such shRNA-protein conjugates are known in the art as taught by Leavitt et al. Limitations of claims 14-16 are mainly functional and related to activity of the conjugate claimed, therefore they are expected to happen in the absence of evidence to the contrary. Further it is noted that the claims are drawn to the method of synthesizing the conjugate, therefore functional limitations of activity of such conjugate are simply inherent to the structure claimed. Limitations related to vaccine in claims 14-16 are functional as well, such limitations simply rename the conjugate claimed as vaccine, which functional characteristics are inherent to its structure.
Claim(s) 1, 11-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN 113355288, September 2021, cited from machine translation) and in further view of Ebben et al (WO 2023/023597, claiming priority to 63/234478, filed August 2021), Leavitt et al (US 2009/0123501, May 2009), Daniell et al (US 2016/0331816, November 2016) and Scialo et al (Lung, 2020, 198: 867-877).
Teachings of Li et al, Ebben et al and Leavitt et al are discussed above in relation to claims 1, 11-26.
None of the references teach codon-optimized ACE2 polypeptide comprising extracellular, transmembrane and intracellular domains.
Daniell et al teach codon-optimized sequence of ACE2 (see paragraph [0010]).
Scialo et al describes that ACE2 consists of 805 amino acids and involves extracellular, transmembrane and intracellular domains (see first paragraph on page 869, second column on pages 867 and 870).
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to use codon-optimized ACE2 taught by Daniell et al, which comprises extracellular, transmembrane and intracellular domains as taught by Scialo et al in synthesizing a conjugate as taught by Li et al, Ebben et al and Leavitt et al. One of the ordinary skill in the art would be motivated to do so, because Daniell et al teach effectively codon-optimized ACE2 protein.
Claim(s) 1, 11-26, 28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN 113355288, September 2021, cited from machine translation) and in further view of Ebben et al (WO 2023/023597, claiming priority to 63/234478, filed August 2021), Leavitt et al (US 2009/0123501, May 2009), Zhao et al (Topics in Current Chemistry 2020, 378:41, pages 1-42).
Teachings of Li et al, Ebben et al and Leavitt et al are discussed above in relation to claims 1, 11-26.
None of the references teach ligating ACE2 with 3’ or 5’ end of shRNA by disulfide bond.
Zhao et al teach that one of the common strategies to conjugate a nucleic acid to a protein is amine thiol cross-linking or disulfide coupling (see page 41, Table 1 and Figure 4).
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to conjugate ACE2 protein to shRNA using disulfide coupling as taught by Zhao et al in synthesizing a conjugate as taught by Li et al, Ebben et al and Leavitt et al. One of the ordinary skill in the art would be motivated to do so, because Zhao et al teach disulfide coupling as a common strategy of conjugating a nucleic acid (shRNA) to a protein (ACE2). It is inherent that such conjugation can be done to 5’, 3’ or both termini of shRNA, because shRNA has only two termini, 5’ and 3’.
Claim(s) 1 and 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li et al (CN 113355288, September 2021, cited from machine translation) and in further view of Wickham et al (WO 2021/231827, claiming priority to 63/025220, May 2020) and Rao (US 2012/0183955, July 2012).
Teachings of Li et al are discussed above.
Li et al do not teach liposomal complex 2ACE2-shRNA5/ch1, which according to instant specification comprises shRNA comprising strand of SEQ ID NO: 49 and liposome comprising DOTAP and cholesterol.
Wickham et al teach siRNAs targeting SARS-CoV-2, including siRNA with one strand of SEQ ID NO: 2355, which is fully complementary to instant SEQ ID NO: 49, and the other complementary strand, identical to instant SEQ ID NO: 49 (see paragraphs [0008-0009], sequence listing). Such siRNA can be in a form of shRNA (see paragraph [0148]) and can be conjugated with peptides (see paragraph [0010]). siRNA can be delivered to cells using lipids (see paragraph [0011]) such as DOTAP (see paragraph [0055]) and cholesterol (see paragraph [0053]).
Rao teaches delivery of shRNAs using DOTAP and cholesterol comprising liposome (see paragraph [0035]).
It would have been obvious to one of the ordinary skill in the art before the effective filing date of the claimed invention to conjugate shRNA taught by Wickham et al to ACE2 protein taught by Li et al and encapsulate such conjugate in a liposome as taught by Rao, arriving at instant invention. One of the ordinary skill in the art would be motivated to do so because Li et al teach a cell expressing two compounds targeting SARS-CoV-2: ACE2 protein capable of binding to the virus and siRNA capable of destroying viral genome, therefore treating the viral infection, motivating one of the art to combine both elements taught by Li et al in one conjugate by attaching ACE2 proteins to both ends of shRNA so that ACE2 protein targets the siRNA to viral particle, because such shRNA-protein conjugates are known in the art as taught by Wickham et al. One would be motivated to encapsulate the conjugate in a liposome comprising DOTAP and cholesterol, because those lipids are suggested for siRNA delivery by Wickham et al and such liposomes are used for shRNA delivery by Rao.
Double Patenting
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.
Claims 1, 11-29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/054,212. Claims from ‘212 recite method of preparation of conjugates of shRNAs targeting SARS-CoV-2 and ACE2 proteins, same as instant invention. Such siRNA can be identical to instantly claimed ones: for example, SEQ ID NO: 16 of ‘212 is identical to instantly claimed SEQ ID NO: 16.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EKATERINA POLIAKOVA whose telephone number is (571)270-5257. The examiner can normally be reached Mon-Fri 8-5.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jennifer Dunston can be reached at (571)272-2916. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/EKATERINA POLIAKOVA-GEORGANTAS/Primary Examiner, Art Unit 1637
Prosecution Insights