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 .
Status of Claims
Claims 1-2, 6, 8, 16, 20, 41, 44-46, 49, 64, 69, 71-72, 74, 81, 85, 88, 92-94, 106, 109-110, 115, 135, 137, 139, 144, 146, 148, 155-158, 161, and 199-200 are pending.
Priority
Instant application 18/115,895, filed 03/01/2023 claims priority as follows:
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Information Disclosure Statement
All references from IDS(s) received 07/11/2023, 02/22/2024, 01/09/2025, 11/19/2025, and 04/14/2026 have been considered unless marked with a strikethrough.
Response to Amendment/Arguments
The amendment filed 04/14/2026 has been entered. Claims 1, 2, 8, 69, 71, 155, and 157 are amended. Claim 134 has been cancelled.
Claims 71, 72, 74, 81, 85, 88, 92, 106, 109, 110, 134, 146, 148, 155, 157, and 199 were rejected under 35 U.S.C. 102(a)(2) as being anticipated by Zhang et al. (WO2022142477A1; filed 15 September 2021). In view of the amendment canceling at least Compound 7 from claim 157 and narrowing the options for Base B in claim 71 to
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, applicant has overcome the previous rejection. Therefore, the previous rejection under section 102 is withdrawn.
Scope of Examination
In the Non-Final rejection dated 01/13/2026, the elected species (compound 5) was previously searched and applicable prior art was not identified. The previous search was therefore extended, in order of the compounds listed in claim 157, to compound 6:
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and applicable prior art was not identified. The previous search was therefore extended again to compound 7:
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and applicable prior art was identified.
However, in view of the amendment filed 04/14/2026 canceling at least Compound 7 from claim 157 and narrowing the options for Base B in claim 71 to
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, the scope of examination has been extended again. In particular, the search was extended to the entire genus of Formula B in claims 71, 72, 74, 81, 85, 88, 92-94, 106, 109-110, 115, 135, 137, 139, 144, 146, 148, 155, and 199; and applicable prior art was not identified. Therefore, the search was extended to the species recited in claim 69 and applicable prior art was not identified. The search was therefore further extended and applicable prior art was identified for the compound:
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.
The above compound reads on claims 1-2, 20, 41, 44, 49, 64, and 158.
Examination has been limited to the scope identified above. Claims 6, 8, 16, 45, 46, 161, and 200 remain withdrawn.
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 71-72, 74, 81, 85, 88, 92-94, 106, 109-110, 115, 135, 139, 144, 146, 148, and 199 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 claims contain 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. Specifically, this rejection concerns the scope of the Formula B variable RK (see e.g. claim 71, line 6).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus …”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed genus is sufficient. See MPEP § 2163. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
In the instant case, the claims at issue are drawn to a compound of Formula B:
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wherein the variables RA, RB, RC, and base B are defined in the claim. When Base B is
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or
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, the variable RK is selected from C₆-C₁₀ aryl, -O-C6-C10 aryl, -O-C1-C10 alkyl, or C1-C₁₀ alkyl optionally substituted with -OP(=O)(OH)(ORL).
The Formula B variable RK in amended claim 71 is unsupported by the disclosure. The specification describes 10 working example compounds to support Formula B (Specification, [0091], Compounds 5-11 and 13-15). Of the 10 examples, zero comprise the base
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; and two comprise the base
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. See the two compounds below, referred to as compound 5 and compound 6:
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The above two compounds, which provide the only working example support for the instant claims when base B is
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or
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, fail to provide support for compounds of Formula B where RK is C₆-C₁₀ aryl, -O-C6-C10 aryl, -O-C1-C10 alkyl, or C1-C₁₀ alkyl optionally substituted with -OP(=O)(OH)(ORL). The aforementioned compounds only provide support for compounds of Formula B where RK is -CH2- substituted with -OP(=O)(OH)(ORL).
A correlation between the claimed genus (comprising the full RK scope) and the disclosed function (orally bioavailable compounds for treating viral infections) has not been established by the prior art; nor has the correlation been sufficiently disclosed by applicant. The skilled artisan must rely upon applicant’s disclosure in order to predict which of the many possible compounds embraced by claim the claims possess the claimed function.
However, Applicant has not explored and disclosed a representative number of species to adequately establish such a correlation. Instead, only two embodiments are disclosed by applicant; and only one was tested for its oral bioavailability. Compound 5 is an intermediate in the synthesis of compound 6 (see [0277] of the Specification). Compound 6 is a prodrug containing an N-methylene phosphate promoiety which undergoes cleavage in vivo to release the known drug compound GS-441524, referred to as “Reference compound A” in the specification (Specification, page 89, [0298]):
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Both compounds comprise an N-methylene phosphate promoiety. No other RK group was assessed (such as C₆-C₁₀ aryl, -O-C6-C10 aryl, -O-C1-C10 alkyl, or unsubstituted C1-C₁₀ alkyl). Applicant’s own results with compound 6 underscore the unpredictability associated with structural changes to Base B. See Table F1 in the specification, which shows that introducing the N-methylene phosphate promoiety (compound 6) results in higher oral bioavailability at a lower dose when compared with the ester reference compound where “RK” is -H.
The N-methylene phosphate promoiety is known in the prior art and the person having ordinary skill understands that cleavage of that moiety occurs in vivo by alkaline phosphatase to release the active drug. See, for example, MEANWELL (Chemical Society Reviews, vol. 53, no. 4, Feb. 2024, pp. 2099–210). Meanwell discloses (Table 37, starting at page 2184) a compendium of prodrugs approved by FDA or other regulatory agencies during the period of 2018-2022. The table includes known approved prodrugs such as fostamatinib (2018) and fostemsavir (2020):
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See also fosphenytoin in Table 2 on page 2106:
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Therefore the prior art establishes a known correlation when RK comprises C1-C10 alkyl substituted with -OP(=O)(OH)(ORL).
But when RK comprises a bond to a C₆-C₁₀ aryl or unsubstituted C1-C₁₀ alkyl with no path to cleavage, or an N-O bond when RK is -O-C6-C10 aryl, -O-C1-C10 alkyl, the person having ordinary skill has no basis for predicting the activity of such compounds due to a lack of correlation between structure and function. These RK variables appear to be more appropriate and supported when Base B is
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, but that base has been removed from the claim genus in the amendment filed 04/14/2026.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”)
Accordingly, the specification fails to provide adequate written description for the genus of claims 71-72, 74, 81, 85, 88, 92-94, 106, 109-110, 115, 135, 139, 144, 146, and 148 and does not reasonably convey to one skilled in the relevant art that the inventors, at the time the application was filed, had possession of the entire scope of the claimed invention.
Please note: In the interest of compact prosecution, the examiner recommends amending claim 71 to incorporate the RK definition from pending claim 137 in order to overcome the rejection.
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.
The factual inquiries 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.
Claims 1-2, 20, 41, 44, 49, 64, and 158 are rejected under 35 U.S.C. 103 as being unpatentable over SHEN (US 20240166680 A1; published 23 May 2024; effectively filed 15 April 2021).
Shen discloses nucleoside analogs and pharmaceutical compositions thereof useful for treating and/or preventing a disease caused by viral infections (Shen, Abstract). Shen discloses compounds having the formula I-VIII (page 3, right side):
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wherein R2 is defined in [0013] and R5 is defined in [0016]. The genus disclosed in Shen overlaps with instantly claimed Formula A where R1 and R2 are taken together to form -OCHR6O-; R3 is -C(=O)R7; Base A is
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; and R12 is H. Shen also discloses particular compounds such as A35, A36, C17, and C18 (pages 8 and 19):
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The above compounds A35 and A36 only differ from Formula A by the identity of Base A: in Shen, the base is a pyrimidine; and in Formula A, the base is a pyrrolotriazine. Alternatively, compounds C17 and C18 only differ from Formula A by the lack of an ester on the 5’-OH substituent.
Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying at least KSR example rationale (B), it would have been prima facie obvious to substitute the pyrimidine base in compound A35 or A36 with a pyrrolotriazine in view of Shen’s teachings. Alternatively, it would have been prima facie obvious to substitute the free 5’-OH group with an isobutyl ester in view of Shen’s teachings. A person having ordinary skill would have enjoyed a reasonable expectation that the either substitution would have resulted in compounds having antiviral activity. See also MPEP 2144.09: “A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. ‘An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.’ In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
The aforementioned compounds are considered obvious structural variants of those disclosed in Shen in view of the overlapping genus and the teachings identified above; and the instant specification provides no evidence of unexpected activity for these compounds.
Accordingly, claims 1-2, 20, 41, 44, 49, 64, and 158 are rejected.
Allowable Subject Matter
Claims 69, 137, and 155-157 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The instant claims are drawn to compounds such as:
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(compound 5); and
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(compound 6).
Compound 5 is an intermediate in the synthesis of compound 6 (see [0277] of the Specification). Compound 6 is a prodrug containing an N-methylene phosphate promoiety and is disclosed as having utility for treating certain viral infections. Compound 6 is compared in the specification with prior art compounds referred to as “Reference compound A” and “Ester Reference Compound”:
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Reference compound A is also known as GS-441524. Ester reference compound is a prodrug of GS-441524 known as ATV006 or obeldesivir.
Close prior art is ZHANG (WO 2022142477 A1; filed 15 September 2021; previously cited). Zhang originally disclosed ATV006 (Zhang, page 46, [00181]) for treating viral infections and demonstrated its superior bioavailability in both rats and non-human primates as compared with GS-441524 (Zhang, page 68, [0024]; 30% ATV006 vs 8.3% GS-441524). ATV006 is an orally bioavailable prodrug of GS-441524.
Zhang’s ATV006 differs from instant compound 6 by the N-methylene phosphate promoiety. The use of an N-methylene phosphate group as a promoiety is not new. For example, BYUN (WO 2021262826 A2; published 17 February 2022) discloses 1’-cyano nucleoside analogs for treating viral infections, and particularly discloses compound 28:
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.
Compound 28 is an analog of remdesivir, which is a different prodrug (administered intravenously) of GS-441524 and has the structure:
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.
While the prior art generally recognized the use of an N-methylene phosphate group as a promoiety in 1’-cyano nucleoside analogs, the prior art fails to teach, suggest or otherwise provide any particular motivation to install that moiety on Zhang’s compound ATV006 in order to arrive at instant compound 6 (or the synthetic intermediate compound 5). Moreover, the Specification provides evidence of unexpected results which are of practical significance. Specifically, Table F1 on page 90 demonstrates that compound 6, when administered to resus monkeys in a lower oral dose (5.75 mg-eq/kg Ref. compound A) compared to ATV006 (10 mg-eq/kg Ref. compound A) resulted in superior efficiency and bioavailability. Compound 6 demonstrates an oral bioavailability of 27.2%, which is a substantial improvement over ATV006’s 18.9%; and achieves this superior bioavailability at roughly half the dose of ATV006. A person having ordinary skill could not have predicted these results from what was known in the prior art about ATV006 at the priority date.
Similarly, the prior art fails to teach, suggest, or otherwise provide any motivation to prepare compound 4:
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recited in claim 69.
Conclusion
Claims 1-2, 20, 41, 44, 49, 64, 71-72, 74, 81, 85, 88, 92-94, 106, 109-110, 115, 135, 139, 144, 146, 148, 158, and 199 are rejected. Claims 69, 137, and 155-157 are objected to. Claims 6, 8, 16, 45, 46, 161, and 200 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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