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 .
Change of Examiner
This application has been reassigned to Examiner Valenrod whose contact information is provided in the conclusion of this office action
Election/Restrictions
Upon further review, the election/restriction requirement set forth in the office action mailed on 3/9/26 is withdrawn. Claims 1-32 are considered on the merits.
References in Specification
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Applicant is advised that should claim 6 be found allowable, claim 15 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof.
Applicant is advised that should claim 23 be found allowable, claim 24 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof.
When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112(b)
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 9 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. Claim 9 recites “wherein R4 and R4 are independently H or F”. There is only one R4 in the compound 1a. It’s unclear what the second R4 refers to.
Claim 26-32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential elements, such omission amounting to a gap between the elements. See MPEP § 2172.01. The omitted elements are: structure compound of Formula 1a is missing.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 2, 27 and 30 recite the broad recitation pneumovirus, and the claim also recites RSV and metapneumovirus which is the narrower statement of the range/limitation. Pneumovirus is a genus while RSV and metapneumovirus are species with that genus. Additionally, SARS-COV-2 is a species of the genus coronavirus. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 1-16, 18, 26-27 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 are directed to a method of inhibiting a respiratory infection, inhibiting RSV, inhibiting or impairing RNA elongation, all in a subject in need thereof. The scope of the term “inhibit” is unclear. Does it include prophylactic administration or only treatment or both? On page 31 the specification recites inhibiting or treating or preventing RSV in a subject in need, but its not clear what the distinction between the three is. Treating already encompasses inhibiting and preventing (see paragraph 2 p 31). For the purposes of this office action, Examiner will interpret inhibit to encompass both prophylactic and curative administration.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claims 17, 19 and 20 recite the broad recitation treating, and the claim also recites preventing which is the narrower statement of the range/limitation. Specification on page 31, paragraph 2, defines treatment to encompass prevention. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim Rejections - 35 USC § 112(a)
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
Claims 1, 2, 4-11, 13-15, 17-21, 23, 23, 26-32 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. At issue is the definition of variable X. The claims recite X is N, C, -NR0, or -CRaRb. Of the 4 recited definition of X only “N” is possible and only compounds with X = N have been tested. X is a part of a 6-membered aromatic ring. There is no evidence applicants have prepared compounds where X is C (which would mean C is positively charged), where X is NR0 (which would result in a highly unstable structure with N being a part of an ammonium ion), or where X is -CRaRb (which would require the carbon atom to exceed its allowed valency). Specification lacks evidence that such compounds have been prepared or that they can be prepared.
Scope of enablement
There are two scope of enablement rejections.
The first one is directed to the scope of the compounds that can predictably be used in the claimed methods.
The second one is directed to the scope of methods in which the compounds can predictably be used.
Claims 1-21, 23-24, 26-32 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 compounds methods and compositions comprising the compounds of claims 22 and 25, does not reasonably provide enablement for compounds compositions and methods encompassed by the scope of the rejected claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
a) Determining if any claimed compounds within the rejected claims would be active would require synthesis of the substrate and subjecting it to testing with Applicants' RNA elongation inhibition assay. Considering the large number of compounds to be made this is a large quantity of experimentation.
b) The direction concerning the claimed compounds is found in on page 18, which merely states Applicants' intent to make and use such compounds.
c) In the instant case none of the working examples (pages 21-23 and 41) contain:
Acidic or basic radicals,
Ring fusions between radicals R0, R1, R2, R3, R4, R5, Ra and Rb,
Radicals where R2 is not an electron withdrawing group larger than CF3.
R3 anything other than Methyl group.
R5 or R6 anything other than hydrogen of halogen
R1 anything other than an optionally substituted benzyl group
d) The nature of the invention is inhibition of RSV viral polymerase and treatment of RSV in subjects by administration of Applicants' compounds. This involves physiological activity. The nature of the invention requires an understanding of the RdRP complex, the binding activity of small ligands to that complex, and the ability of those compounds to inhibit the RdRP. In view of the unpredictability of binding activity and claimed divergent substituents with varied polarity, size, and polarisability, the skilled physician would indeed question the inclusion of such diverse rings, commensurate in scope with these claims. Also see the MPEP § 2164.03 for enablement requirements in the structure sensitive arts of pharmacology and medicinal chemistry.
e) The state of the art is detailed knowledge of the RdPR complex is lacking. The structural requirements of ligands that can inhibit activity of the polymerase have not been established. There is no reasonable basis for the assumption that the myriads of compounds embracing the present formula (1a) will all share the same biological properties. For example, R1 includes basic and acidic groups, groups as small as a hydrogen atom and as large as bicyclic heretocycles with various substituents, which have drastically different steric considerations, groups with various degrees of polarizability and reactive functional groups such as esters. The scope of the R1 is unlimited because the claim encompasses substitution of Rc with any substituent. Same diversity of substituents exists for the rest of the variables within compound 1a. The diverse claimed moieties within of the claimed R groups are chemically non-equivalent and there is no basis in the prior art for assuming in the non-predictable art of pharmacology that structurally dissimilar compounds will have the disclosed activity, In re Surrey 151 USPQ 724 (compounds actually tested which demonstrated the asserted psychomotor stimulatory and anti-convulsant properties were those having the 3,4-dichlorophenyl substituent at the 2-position on the thiazolidone nucleus not sufficient for enablement of any heterocyclic radical at the same position). In re Fouche, 169 USPQ 429 at 434 (a Markush group including both aliphatic and heterocyclic members not enabled for the use of those compounds within the claim having heterocyclic moieties.) In re CAVALLITO AND GRAY, 127 USPQ 202 (claims covering several hundred thousand possible compounds, of which only thirty are specifically identified in appellants' application, not enabled unless all of the thirty specific compounds disclosed had equal hypotensive potency because that fact would strongly indicate that the potency was derived solely from the basic structural formula common to all of them. A wide variation in such potency would suggest that it was due in part to the added substituents and might be eliminated or even reversed by many of the possible substituents which had not been tried.)
Compounds made and tested represent the scope of claims 22 and 25 not claim 1 or the other claims rejected.
f) The artisan using Applicants' invention to treat diseases with the claimed compounds would be a physician with a MD degree and several years of experience. He would be unaware of how to predict a priori how changing a benzyl ring would affect biological activity. In view of the divergent substituents with varied basicity, steric hindrance, and polarisability, the skilled physician would indeed question the inclusion of such diverse groups of substituents, commensurate in scope with these claims.
g) Physiological activity, is well-known to be unpredictable, In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) (contrasting mechanical and electrical elements with chemical reactions and physiological activity). See also In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993); In re Vaeck, 947 F.2d 488, 496, 20 USPQ2d 1438, 1445 (Fed. Cir. 1991).
h) The breadth of the claims includes all of thousands of compounds of formula (1a). Thus, the scope is very broad. The present claims embrace various radicals, which are not art-recognized as equivalent. The specific compounds made are not adequately representative of the compounds embraced by the extensive Markush groups instantly claimed.
MPEP 2164.01(a) states, “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).” That conclusion is clearly justified here. Thus, undue experimentation will be required to practice Applicants' invention.
Claims 37-41, 43, 44 and 48-53 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. While the clams are enabled for treating RSV in a subject who is infected with RSV, claims are not enabled for treatment or prevention of other respiratory diseases and disorders.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to: (a) the nature of the invention; (b) the breadth of the claims; (c) the state of the prior art; (d) the amount of direction provided by the inventor; (e) the existence of working examples; (f) the relative skill of those in the art; (g) whether the quantity of experimentation needed to make or use the invention based on the content of the disclosure is "undue"; and (h) the level of predictability in the art (MPEP 2164.01 (a)).
Nature of the invention and Breadth of the claims:
The claims are directed to a method of:
Inhibiting a respiratory infection or disease (claims 1, 11, 16) with a more limited list of specific viruses in claim 2 and inhibiting RSV in claim 18.
Treating or preventing a respiratory infection or disease (claim 17, 19).
Inhibiting or impairing RNA elongation of viral RNA in a subject in need (claim 26).
Method of blocking viral RNA-dependent RNA polymerase of a virus in a subject in need (claim 29).
All rejected claims require administration of compound 1a to a subject in need. Examiner is interpreting all claims to be directed to a method of achieving therapeutic efficacy by administering compound 1a and all claims to encompass prophylactic administration.
it is incumbent upon Applicant to teach the skilled artisan how to treat and prevent any respiratory disorder and every specific virus listed in claim 2 according to the method 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 treat cancer without undue experimentation.
State of the prior art and level of predictability in the art:
Tian et al (European Journal of Medicinal Chemistry, 2021, 213, 113201) represents state of the art with regards to RNA-dependent RNA polymerase (RdRp) inhibitors. Art does acknowledge that RdRp is an attractive target for treatment of RNA-based viruses. However, art also demonstrates that implementation of this strategy has thus far not resulted in approved treatment. Compound 1a of the current claims is described in the specification as having RdRp-inhibitory activity. Compound 1a is a non-nucleoside inhibitor (NNI). Such inhibitors are described on pages 9-12 of Tian. Tain describes various allosteric sites for activity of the inhibitors and presents data on past NNis and their clinical studies progress. In Table 4, out of 26 trials conducted none is available as a therapeutic agent for treatment of a viral infection. This demonstrates that whether any specific NNI RdRp inhibitor will actually find utility in treatment of a viral infection is highly unpredictable.
Amount of direction provided by the inventor and existence of working examples:
Applicants have demonstrated activity of a select number of species within the scope of compound 1a. The activity is limited to reducing replication of RSV. To reduce replication of RSV, a subject must already be infected with RSV. There is no data to suggest that administration of compound 1a prevents infection from taking place. There is also no data on any other respiratory infection or disease or any other respiratory virus. Due to variability of RNA polymerase structures among different RNA viruses it’s not possible to predict whether replication of any other virus can be inhibited by administration of compound 1a.
Although, the specification need not contain an example if the invention is otherwise disclosed in such manner that one skilled in the art will be able to practice it without an undue amount of experimentation. In re Borkowski, 422 F.2d 904, 908, 164 USPQ 642, 645 (CCPA 1970), lack of a working example is a factor to be considered, especially in a case involving an unpredictable and undeveloped art.
Relative skill of those in the art and quantity of experimentation needed to make or use the invention: Although the relative level of skill in the art is high, one of ordinary skill would not be able to treat or prevent any respiratory disorder other than RSV according to the claimed method without engaging in undue experimentation. The art clearly recognizes that the therapeutic outcome of RdRp inhibition strategy is highly unpredictable and generally fails. Thus, without specific guidance as to what patient population should be treated according to the method, the skilled artisan must experiment to identify a population that might reasonably be expected to respond. Thus, without specific guidance as to an effective dosage and route of administration of the agent, assuming that one exists, and the additional manipulations required for effective therapy, one of ordinary skill in the art must experiment to establish effective parameters. Given the complexity and unpredictability inherent to pharmacological science and lack of data supporting the broad clinical application of compound 1a, the amount of experimentation required would clearly be undue.
Thus, given these considerations, one of ordinary skill in the art clearly would not be able to practice the claimed method such that it can be used as contemplated in the specification without first engaging in substantial and undue experimentation. Therefore, the claims are rejected under 35 U.S.C. §112, first paragraph, as lacking and enabling disclosure.
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.
Claim(s) 21-25 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Plemper et al (US 2019/0144441).
Compound AVG-233 on page 118 is the first compound of claims 21 and 25. Potency testing on page 123 requires preparation of a solution comprising the compound and therefore meets the limitations directed to pharmaceutical composition.
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) 1-20 and 26-32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Plemper et al (US 2019/0144441).
Scope of prior art
Plemper teaches compound AVG-233 (p 118) and its inhibitory activity (page 123). AVG-233 has potency grade A, indicating it’s one of the more potent compounds. Plemper discloses utility of the disclosed compounds in treatment of RSV (abstract, paragraph [0012]). Mosed of administration are in paragraphs [0061])
Ascertaining the difference
Plemper teaches compound AVG-233 and suggests treatment of RSV in a subject by administering AVG-233. However, there are many compounds described in Plemper and no examples where a subject is treated with AVG-233 are present.
Obviousness
A person of ordinary skill in the art, prior to the earliest effective filing date of the current application, would have found it obvious to try administering compound AVG-233 of Plemper to a subject with RSV infection. It would have been obvious to select AVG-233 because Plemper indicates it as one of the more potent compounds tested. There is suggestion to treat RSV in paragraph [0012]. There is expectation of success because a compound with similar activity has shown activity in RdPd reporter assay virus inhibition assay (Figures).
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 1-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. 10,906,899. Although the claims at issue are not identical, they are not patentably distinct from each other because: Claim 19 of ‘899 is directed to a pharmaceutical composition comprising the currently claimed compound (4th compound in claim 19 of ‘899). Claims 1-15 of ‘899 are directed to a method of treating an RSV infection comprising administering generic compound 1b, which encompasses the currently claimed compounds and AVG-233.
Conclusion
Claims 1-32 are pending
Claims 1-32 are rejected
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YEVGENY VALENROD whose telephone number is (571)272-9049. The examiner can normally be reached Mon-Fri 9am-5pm.
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, Amy L Clark can be reached at 571-272-1310. 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.
/YEVGENY VALENROD/Primary Examiner, Art Unit 1628
Prosecution Insights