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 .
Election/Restrictions
Applicant’s election of group 1 with species PEDV (elected) in the reply filed 9/3/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 4, 9, 11, 16-21, 23-46 and 48-92 have been cancelled.
Claims 1-3, 5-8, 10, 13-15, 22, and 47 are pending.
Claims 22 and 47 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-3, 5-8, 10, and 13-15, drawn to a vaccine composition comprising a coronavirus comprising mutations in at least two non-structural proteins comprising Nsp1, 15, and 16 having the sequences of SEQ ID NOs: 4, 8 and 12, are examined on merits.
In this Office action, NSP, Nsp and nsp are interchangeable.
Information Disclosure Statement
The information disclosure statement (s) (IDS) submitted 7/24/2023 are considered by the examiner and initialed copies/copy of the PTO-1449 are/is enclosed.
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.
Written Description:
Any one mutated in two nonstructural proteins (NSPs) in a coronavirus used as a vaccine to induce an immune response
Claims 1-3, 5-8, 10, and 13-14 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Possession may be shown. For claimed product the specification must provide sufficient distinguishing identifying characteristics of the genus, including disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, level of skill and knowledge in the art, and predictability in the art or any combination thereof.
The claims are broadly drawn to
A vaccine composition comprising a coronavirus comprising at least one mutation in at least two nonstructural proteins, wherein said vaccine composition is capable of inducing an immune response in a subject,
Wherein the vaccine composition, wherein the nonstructural proteins are selected from the group consisting of Nsp1, Nsp15 and Nsp16,
Wherein the coronavirus is porcine epidemic diarrhea virus (PEDV, elected)
Thus, the claims are including vaccines comprising genus of mutated nonstructural protein at any locations, that induce immune response in a subject.
The specification teaches that porcine epidemic diarrhea virus (PEDV) belong to coronavirus and emerged suddenly in the US in 2013 causing immense losses in swineherds. The specification also cites reference showing d that inactivating Nspl6 in combination with a deletion in the spike glycoprotein in the PEDV-22A strain generated a virus that exhibited reduced pathogenesis, but still caused diarrhea in piglets (page 2). The specification further states that endoribonuclease (ENdoU) plays a role in pathogenesis of coronavirus and inactivating EndoU/Nspl5 in PEDV was found to be sufficient to elicit both type I and type III interferon responses from infected cells, and reduce clinical disease in infect piglets (page 3).
However, the inactivation of this single interferon antagonist was not sufficient to fully attenuate PEDV, as the infected piglets still exhibited some diarrhea. In addition, the PEDV Nsp1 (F44A) mutation was shown to reduce the ability of Nsp1 to antagonize the activation of interferon in an overexpression system in cultured cells, but the effect of this mutation in the context of virus replication was unknown.
The specification summarizes the invention comprising a composition comprising nonstructural proteins, one or more Nsp1, Nsp15 or Nsp16 with one or more mutation, specifically one mutation in Nsp1, two mutations in Nsp15 and one mutation in Nsp16 (page 4). The specification also teaches specific mutations in PEDV virus including
F44A of Nsp1 as set forth in SEQ ID NO: 4; H226A and H241A of Nsp15 as set forth in SEQ ID NO: 8; D129A of Nsp16 as set forth in SEQ ID NO: 12, which in combination in a vaccine composition is capable of inducing IFN production and neutralizing antibody response (page 5 and examples).
Thus, the specification describes vaccine composition specific for coronavirus PEDV infection wherein the vaccine has specific mutations located in Nsp1, 15 and 16, but not teach any mutation within the non-structural protein could be used as vaccine as claimed.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common the genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The Federal Circuit has recently clarified that a DNA molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that the written description requirement can be met by “show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristic, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. “ Id. At 1324, 63 USPQ2d at 1613”.
The court has since clarified that this standard applies to compounds other than cDNAs. See University of Rochester v. G.D. Searle & Co., Inc., F.3d ,2004 WL 260813, at *9 (Fed.Cir.Feb. 13, 2004). The instant specification fails to provide sufficient descriptive information in the broadly claimed coronavirus vaccine comprising any Nsp proteins with any mutations at any location that could perform a function of inducing immune response. Thus, one of skill in the art would reasonably conclude that the inventor(s), at the time the application was filed, did not have possession of the claimed invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided:
The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the “written description” inquiry, whatever is now claimed.
As stated in the Written Description Guideline (2008), the levels of the skill and knowledge in the art would not be able to identify without further testing which of these broadly claimed Nsp protein could perform as vaccine fo coronavirus PEDV infection. Based on the lack of knowledge and predictability in the art those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of the vaccine composition based on the teaching of mutations F44A of Nsp1; H226A and H241A of Nsp15, and D129A of Nsp16 as set forth in SEQ ID NOs: 4, 8 and 12.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure(s) and functional attribute(s) of the encompassed genus of functional variants having at least 80% sequence identity as claimed, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only the PEDV vaccine composition comprising mutations F44A of Nsp1, H226A and H241A of Nsp15, and D129A of Nsp16 as set forth in SEQ ID NOs: 4, 8 and 12 respectively, but not the full breadth of the claims, meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Applicant may also refer to Written Description Guideline at USPTO website:
http://www.uspto.gov/web/patents/guides.htm
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
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.
1. Claim(s) 1-3 and 5-6 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by or, in the alternative, under 35 U.S.C. 103 as being unpatentable over Bouvet et al (JBC 289: p25783-796, 2014) as evidenced by Hou et al (JV 93: e00406, Aug 2019).
Bouvet et al teach non—structural proteins (nsp) 1-16, wherein the nsp-10 interact with nsp14 and nsp16 to stimulate enzyme activities of coronavirus SARS-CoV) for regulation of coronavirus replication (abstract). Bouvet et al then teach mutation(s) with alanine substitutions within the nsp10 protein, nsp14, and/or nsp 16 (table 1, figure 6-7) could disrupt the nsp proteins interactions and reverse the exoribonuclease and 2’-O-methyltransferase 2’-enzymatic activities, which reduce virus amplification and thereof treatment or preventing the virus infection.
For 103 rejection.
Bouvet et al although do not test immune response induced by the mutant nsp proteins, one skilled in the art would understand mutation of nsp protein including nsp16 by disrupting the function or inactivation of 2’-O-MTase of nsp 16 protein would result in reducing antagonist function of the nsp protein that would induce immune response in vivo as evidenced by Hou et al, who teach mutations of nsp16 inducing production of IFN-α, β, and γ and reducing virus replication (page 3-4 and figure 2-4).
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-3, 5-8, 10, and 13-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hou et al (JV 93:e00406, Aug 2019, IDS dated 7/24/2023, #17) in view of Zhang et al (JV, 92: e01677-17 Feb 2018, IDS dated 7/24/2023, #48), Deng et al (JV, 93: e02000-18, April 2019, IDS dated 7/24/2023, #9) and Zheng et al (JBC 293: 12054-12067, 2018).
Hou et al’s teaching on IFNα, β, and γ induction by mutations of nsp16 is set forth above. Hou et al also teach Porchine Epidemic Diarrhea Virus (PEDV) vaccine that comprises nsp16 mutations 129A, K45A-D129A-K169A-E202A, and Y1378A that could inactivate antagonism of IFN-β pretreatment and induce stronger IFN response in vitro, which also reduce PDEV virus titers ((page 3, figure 3--4).
Hou et al do not teach the mutations of nsp1 and nsp15.
Zhang et al-JV teach type III interferon (IFN-λ) induced by alanine substitution of PEDV nsp1 protein, wherein the mutations include claimed F44A (page 13 and figure 9).
Deng et al also teaching that nsp15 as an endoribonuclease (enUmt) in PEDV suppresses types I and III interferon response, specifically Deng et al teach alanine substitution at 226 (H226A) of nsp15 (abstract) of the virus (figure 1 and bridging page 4-5) and teach specific IFNβ and IFNλ production increased 200-500-folds than the wild type cells (page 6-7 and figure 3-5).
Zheng et al-JBC also teach porcine delta coronavirus (PDCoV) including PEDV amino acid substitution of histamine at nsp15 (H241A, table 1 line 2). The amino acid H241 in Nsp15 is located WT catalytic cites with other amino acids forming a pocket for RNA substrate binding (figure 6A, and page 12059 right col).
The prior arts in combination taught PEDV having the specific amino acid substitutions at nsp1-F44A, nsp15-H226A, nsp1-H241A, and nsp16-D129A as set forth above appear to meet the requirements of the instant claim 15. Regarding with the limitations of the mutant of PEDV Nsp proteins represented by the sequences of SEQ ID NO: 4, 8 and 12, the Office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
The Office has shown a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not" (In re Spada; MPEP 2112.01(I)), Thus, the burden has been shifted to applicant to prove that the product of the prior art does not have the characteristics as-claimed ('characteristics' meaning physical or functional characteristics).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine all the references with all the amino acid substitutions as claimed to form a vaccine for the PEDV infection with expected result. One of ordinary skill in the art before the effective filing date of was made would have been motivated to with reasonable expectation of success to combine all the teachings in order to benefit of preventing PEDV infection in pig or even in human because each of the references teach function lost in the PEDV with substitutions of amino acids with alanine and induction of immune response. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success to do so because each of the references by Hou, Zhang-JV, Deng and Zheng-JBC et al have shown one or more mutations in nsp1, nsp16 and nsp15 and methods of producing the mutated virus. Therefore, the references in combination teach every limitation of the claims and the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the invention was made, absent unexpected results.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
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 (MPEP 9th Ed, Feb 2023).
An obviousness-type double patenting rejection is appropriate where the conflicting claims are not identical, but an examined application claim not is patentably distinct from the reference claim(s) because the examined 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).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Over Application:
Claims 1-3, 5-8, 10, and 13-14 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-7, 9-18 of copending Application No. 18341330 (filed on 6/23/2023). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims are directed to coronavirus vaccine comprising non-structure protein nsp-15 having mutation that affect the activity of nsp15 including immune response.
The instant claims are drawn to
A vaccine composition comprising a coronavirus comprising at least one mutation in at least two nonstructural proteins, wherein said vaccine composition is capable of inducing an immune response in a subject,
Wherein the vaccine composition, wherein the nonstructural proteins are selected from the group consisting of Nsp1, Nsp15 and Nsp16,
Wherein the coronavirus is porcine epidemic diarrhea virus (PEDV, elected)
The claims of application ‘330 are drawn to
A live, attenuated coronavirus comprising a variant replicase gene encoding polyproteins comprising a non-structural protein (nsp)-15, the replicase gene encoding the nsp15 and causing any change, including mutations and/or deletions, that affects the stability or activity of the nsp15 (claim 1),
Wherein coronavirus is PDCov, PEDV…. TGEV…(claim 5),
A vaccine comprising the coronavirus of claim 1 (claim 9).
A method for preventing a disease in a subject, the method comprising administering the vaccine of claim 9 to the subject.
A method of preventing a disease in a subject, the method comprising activating type I interferon in the subject, wherein activation of the type I interferon reduces the pathogenicity of a coronavirus.
Both sets of the claims are drawn to coronavirus vaccine comprising mutation(s) in Nsp15 of PEDV and/or a method of using the mutant Nsp proteins or virus comprising thereof as vaccine for treating or preventing infection with the virus. The difference is that the dependent claims of ‘330 application recites mutation at different location as the instant claimed mutations, but each set of the claims encompass generic claims which comprise mutations. Thus, the difference between the two sets of the claims is the scope of claims with overlapped mutation(s) of Nsp15.
Thus, the claims of instant application and the claims of ‘330 application would anticipate and be obvious over each other.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
No claim is allowed.
The amino acid sequences of SEQ ID NOs: 4, 8 and 12 are free of the prior art based on the search results of the available databases in USPTO.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Lei Yao, whose telephone number is (571) 272-3112. The examiner can normally be reached on 8:00am-6:00pm Monday-Friday.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis, can be reached on (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LEI YAO/Primary Examiner, Art Unit 1642