DETAILED ACTION
The examiner of record has changed. Please direct all further correspondence to ZACHARY J MIKNIS whose telephone number is (571) 272-7008.
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 .
Status of the Application
The claims of 11 July 2023 are entered.
The election of 6 May 2026 is entered.
Claims 1-23 are pending. Claims 6 and 19-23 are withdrawn without traverse. Claims 1-5 and 7-18 are being examined on the merits.
Election/Restrictions
Applicant’s election without traverse of Group I and Z-VEID-FMK in the reply filed on 6 May 2026 is acknowledged.
Claims 6 and 19-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 6 May 2026.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the specification are not identified by sequence identifiers (i.e., “SEQ ID NO:X” or the like) in accordance with 37 CFR 1.831(c). See Claim 5, and p.3, 5-9, 12, 16, 18-19, 28, 44, 46, 48-50, 52, 58-63, and 68 of the specification.
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings. See Figures 4-8, 10, 12-14, 17-18, and 20.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
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 1-4 and 7-18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for treating a coronavirus infection or coronavirus-associated disease in a subject comprising administering a pharmaceutical composition comprising Z-VEID-FMK; AC-VEID-CHO; or caspase-6 targeting ssRNA, siRNA, shRNA, or miRNA, does not reasonably provide enablement for a method of treating a coronavirus infection or coronavirus-associated disease or preventing a coronavirus-associated disease with any capsase-6 inhibitor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
“[T]o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.’” Genentech Inc. v. Novo Nordisk 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997); In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); See also Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir. 1991); In re Fisher 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Further, in In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988) the court stated:
Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman [230 USPQ 546, 547 (BdPatAppInt 1986)]. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredict-ability of the art, and (8) the breadth of the claims.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).
Nature of the Invention
The claims are drawn to two methods. First, treating a coronavirus infection by administering to a subject a pharmaceutical composition comprising a caspase-6 inhibitor that when administered is effective to reduce replication of the coronavirus in the subject. Second, preventing or treating a coronavirus-associated disease by administering the same caspase-6 inhibitor to reduce “replication one or more symptoms of the coronavirus-associated disease in the subject”.
Breadth of the Claims
The claims are broad. The caspase-6 inhibitor language does not limit it to a particular class of compounds, but rather defines the compound by what it does rather than by structure. Treatment of coronaviruses is somewhat broad. Prevention or treatment of a coronavirus-associated disease is broad.
State of the Prior Art
Caspase-6 cleavage of nucleocapsid protein was recognized as a necessity for SARS-CoV-1 lifecycle (see e.g. Diemer et al. J. Mol. Biol. 376:23-34, published 2007).
As further discussed below, the caspase-6 specific inhibitor z-VEID-fmk was recognized in the prior art for inhibition of coronavirus replication (see e.g. Yuen et al. Research Square “Coronaviruses exploit a host cysteine-aspartic protease for efficient replication” doi: https://doi.org/10.21203/rs.3.rs-354943/v1, published 26 March 2021).
There is no art that demonstrates that a caspase-6 inhibitor regardless of structure (1) treats any coronavirus infection or (2) prevents any coronavirus-associated disease.
Relative Skill of those in the Art
The relative skill of those in the art is high.
Predictability or Unpredictability of the Art
There is a general lack of predictability in the pharmaceutical art. In re Fisher, 427, F. 2d 833, 166, USPQ 18 (CCPA 1970).
There similarly is no predictability as to whether a coronavirus infection will result in coronavirus-associated disease, let alone predicting what actual coronavirus-associated disease will actually occur.
Amount of Direction or Guidance Given
The specification discusses a variety of caspase-6 inhibitors in p.16-17. See also p.18-23. It is noted that while antibodies are discussed, they are largely discussed as targeting caspase-6 rather than through description of a specific structure. As noted with respect to antibody production specifically under the written description standard, merely describing an antigen does not provide description for the resultant antibody even if production of an antibody is routine and conventional.
Presence/Absence of Working Examples
Example 1 demonstrates that the pan-caspase inhibitor z-VAD-FMK inhibits replication of MERS-CoV, SARS-CoV-2, SARS-CoV-1, HCoV-229E, and HCoV-0C43. The Caspase-6-specific inhibitor Z-VEID-FMK is shown to limit MERS-CoV replication, as well as other coronaviruses. Z-VEID-FMK is demonstrated to inhibit N protein production and N gene expression. MERS-CoV infection was limited in organoids and animal models with Z-VEID-FMK administration. Similarly, Z-VEID-FMK administration is shown to be effective in golden hamster models of SARS-CoV-2 infection.
Example 2 indicates that caspase-6 action on the N protein occurs after viral entry. The utility of RNAs targeting capsase-6 specifically is also discussed.
Example 3 shows that caspase-6 specifically targets the N protein.
Quantity of Experimentation Necessary
With respect to treating a coronavirus infection with any caspase-6 inhibitor, the burden placed on the skilled artisan is high. While Z-VEID-FMK is demonstrated to be effective, it represents only a single example of a caspase-6 inhibitor that does not reasonably extend to all other members of the disparate genus. For instance, this does not enable treatment with an antibody targeting caspase-6, especially given that only limited specific antibodies are disclosed that do not provide support for an entire sub-genus of compounds. Similarly, there is no data to support an entire small molecule genus of capsase-6 inhibitors. In all cases, outside the limited disclosed species the onus is left on the skilled artisan not only to define and synthesize the caspase-6 inhibitor, but also to demonstrate it is a caspase-6 inhibitor and also serves to inhibit coronavirus replication in vivo. The collective effort for such experimentation is undue.
With respect to prevention of coronavirus-associated disease, not only are all of the issues present as discussed above with respect to the breadth of caspase-6 inhibitors leading to undue experimentation by itself, but one of ordinary skill in the art also must be able to determine what diseases might occur in order to demonstrate that they are prevented. As argued above, there is no predictability in what coronavirus-associated diseases may or may not occur in any given patient for any given coronavirus infection. Accordingly, it is not possible to show that a caspase-6 inhibitor actually prevented the disease. The level of experimentation is undue because of this unpredictability, combined with the breadth of compounds as claimed.
In view of the Wands factors as discussed above, it is the Examiner’s opinion that the claims are not fully enabled and one of skill in the art would have to engage in undue experimentation to practice the invention as claimed herein, without a reasonable assurance of success.
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.
Claim 5 is 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.
Regarding claim 5, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. This is similar to “for example”, “or the like”, and “such as” as discussed in MPEP § 2173.05(d).
Claim Rejections - 35 USC § 102
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 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.
Claims 1-5 and 7-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yuen et al. (Research Square “Coronaviruses exploit a host cysteine-aspartic protease for efficient replication” doi: https://doi.org/10.21203/rs.3.rs-354943/v1, published 26 March 2021, hereafter referred to as Yuen).
The Yuen art discloses that inhibition of caspase-6 attenuates lung pathology and body weight loss in SARS-CoV-2 infected golden Syrian hamsters and improves survival of MERS-CoV infected human DPP4 knock-in mice (see e.g. Abstract). Yuen more specifically discloses that the pan-caspase inhibitor z-VAD-fmk limits MERS-CoV replication, as well as that of SARS-CoV-2, SARS-CoV-2, HCoV-229, and HCoV-OC43 (see e.g. lines 96-101). The pan-caspase inhibitor is reasonably also a caspase-6 inhibitor. However, Yuen also discloses that the caspase-6 specific inhibitor z-VEID-fmk inhibits replication of all tested coronaviruses, including in human intestinal organoids (see e.g. lines 108-111 and 119-121). The effect was verified in infected mice models (see e.g. lines 127-132). This anticipates claim 1.
With respect to claim 2, as noted above z-VEID-fmk inhibits replication, i.e. by necessity the replication is reduced compared to an untreated patient.
With respect to claims 3-5, as noted above Yuen discloses z-VEID-fmk as being a caspase-6-specific inhibitor.
With respect to claim 7, z-VEID-fmk is shown to reduce coronavirus replication by more than 50% 24 hours following administration (see e.g. Figure 1e).
With respect to claim 8, z-VEID-fmk was administered at 12.5 mg/kg/day, reading up on “from about 7.5 mg/kg/day” (see e.g. Figure 2g).
With respect to claim 9, Yuen shows administration of z-VEID-fmk concurrent with MERS-CoV infection, i.e. within the ranges as claimed (see e.g. Figure 2g).
With respect to claim 10, intraperitoneal administration is disclosed by Yuen (see e.g. Figure 2g).
With respect to claim 11, as noted above Yuen discloses inhibition across coronaviruses.
With respect to claim 12, Yuen suggests that the N protein of transmissible gastroenteritis coronavirus and porcine epidemic diarrhea virus are susceptible to cleavage by caspase-6 similar to other coronaviruses. One of ordinary skill in the art could have at once envisioned treatment of these non-human coronaviruses in line with the z-VEID-fmk treatment of human coronaviruses by targeting the identical pathway of N protein processing.
With respect to claim 13, as noted above Yuen discloses MERS-CoV, SARS-CoV-1, and SARS-CoV-2 inhibition.
With respect to claims 14 and 15, SARS-CoV-2 variants do not generally alter the N protein, i.e. one of ordinary skill in the art could at once envision treatment of the variants since caspase-6 processing is still required.
With respect to claim 16, the coronaviruses discussed by Yuen are generally human coronaviruses, i.e. treatment of a human would be at once envisioned given the targeting of the coronaviruses.
With respect to claim 17 and 18, MERS-CoV is known to proceed to pneumonia, i.e. treatment of the underlying MERS-CoV infection would reasonably be expected to also treat the coronavirus-induced pneumonia (for evidence, see e.g. Memish et al. Lancet 395:1063-1077, published 4 May 2020).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY J MIKNIS whose telephone number is (571)272-7008. The examiner can normally be reached M-F 9-5.
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, Melissa Fisher can be reached at (571) 270-7430. 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.
/ZACHARY J MIKNIS/Patent Examiner, Art Unit 1658
Prosecution Insights