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 .
Detailed Action
This application claims benefit of provisional application 63/413192, filed October 4, 2022. Claims 1-24 are pending in this application and examined on the merits herein. Applicant’s preliminary amendment submitted February 15, 2024 is acknowledged wherein claims 3-12, 14, 16, and 17 are amended.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 24 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.
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, claim 24 recites the broad recitation “Integrase inhibitor” and “HIV capsid inhibitor,” and the claim also recites “(e.g. bictegravir, dolutegravir, cabotegravir, GS-6212)” and “(e.g. lenacapavir)” which is the narrower statement of the range/limitation. 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 § 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.
Claims 1-3, 5, 8, 12-16, 18, 20, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Weber (PCT international publication WO2022/066882, Reference included with PTO-892) in view of Gunaga et al. (Reference included with PTO-892)
Independent claim 1 is directed to a compound which is a 2’-deoxy-4’-alkynyl thionucleotide or thionucleoside having one of several nucleobases defined as “het”. Weber discloses reverse transcriptase inhibitors useful for treating cancer. (p. 2 last paragraph) These compounds are 4’- substituted nucleosides having formula (A):
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. (P. 7 paragraph 33) B is furthermore selected from the following structures
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. (p. 7 paragraph 34) R1 is selected from a list including H. (p. 7 paragraph 35) R12 is selected from a group including ethynyl. (p. 7 paragraph 36) R3-6 are selected from relatively narrow lists including options consistent with the “het” structures in present claim 1. Therefore the compounds of present claim 1 fall within the broad disclosure of compounds described by Weber, with the exception of containing an oxygen rather than a sulfur in the deoxyribose ring. While Weber does not specifically describe a compound anticipating the scope of present claim 1, the reference describes a number of specific compounds. (pp. 9-11 paragraph 49) These include compounds 9
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and 12
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which differ from the compounds of present claim 1 only in that they lack the thiosugar group.
However, Gunaga et al. discloses that 4’-thionucleosides have the same configuration as 4’- oxonucleosides but have inherent advantages such as increased metabolic stability. (p. 2585 left column last paragraph) Various 2’- deoxy thionucleosides structures have been synthesized and developed as antitumor therapeutics (pp. 2496-2623, section 3) It would have been obvious to one of ordinary skill in the art at the time of the invention to make 4’- thionucleotide derivatives of compounds 9 and 12 of Weber. One of ordinary skill in the art would have seen the disclosure of Gunaga et al. as suggesting that this chemical modification is useful for improving the metabolic stability of nucleoside therapeutics including antitumor compounds, and furthermore that it has been successfully used in a variety of structurally similar compounds.
Regarding dependent claims 2, 3, 5, 8, 12-16, and 18, these claims are similarly obvious as they merely specify additional structural features or species previously described by Weber as discussed above. Regarding dependent claim 20, which is directed to a pharmaceutical composition, Weber describes administering the compound as part of a pharmaceutical composition. (p. 46 paragraph 280) Regarding claim 21 which requires a further active agent in the pharmaceutical composition, Weber further describes the pharmaceutical composition comprising an additional therapeutic agent. (p. 46 paragraph 281)
For these reasons Weber in view of Gunaga et al. renders the claimed invention prima facie obvious.
Claims 6, 7, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Weber in view of Gunaga et al. as applied to claims 1-3, 5, 8, 12-16, 18, 20, and 21 above, and further in view of Mehellou et al. (Reference included with PTO-1449)
The disclosures of Weber and Gunaga et al. are discussed above. Weber in view of Gunaga et al. does not disclose a nucleoside having a phosphoarmidate at the 5’- position. (R2 in the present claims) However, Mehellou et al. discloses that nucleoside therapeutics including cancer therapeutics exert their biological activity by activation with nucleoside and nucleotide kinases inside the cell. (p. 2211 left column first paragraph) This process can be inefficient due to structural differences from native nucleosides, often leading to poor bioavailability. (p. 2211 left column second paragraph) Mehellou et al. further describes ProTide® derivatives of nucleoside drugs which include a monophosphate in which the anionic oxygen groups are masked. (p. 2212 right column second paragraph) These include aryloxy phosphoramidates. (p. 2213 table 1 stage 6, p. 2214 right column second paragraph) This prodrug modification has been applied to a wide spectrum of nucleoside drugs. (p. 2218 left column section 5) In one instance, Mehellou et al. discloses the clinical candidate GS-5734 (p. 2218 figure 10 compound 3) which has the same phosphoramidite moiety recited in present claim 19.
It would have been obvious to one of ordinary skill in the art at the time of the invention to make ProTide® phosphoramidite derivatives of the compounds described by Weber in view of Gunaga et al. One of ordinary skill in the art would have seen Mehellou et al. as suggesting that this particular chemical modification is useful for applying to a wide variety of different nucleoside parent drugs including antitumor compounds.
Claims 1-5, 8, 12-16, 18, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Ohrui et al. (PCT international publication WO00/69876, Reference included with PTO-1449) in view of Gunaga et al. (Reference included with PTO-892)
Independent claim 1 is directed to a compound which is a 2’-deoxy-4’-alkynyl thionucleotide or thionucleoside having one of several nucleobases defined as “het”. Ohrui et al. discloses 4’-ethynyl nucleosides for treating HIV. (p. 3 second paragraph) These compounds are 4’- substituted nucleosides having formula (I):
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(P. 7 paragraph 33) wherein B is a purine or pyrimidine, X can be H, and R can be H or a phosphate. Therefore the compounds of present claim 1 fall within the broad disclosure of compounds described by Ohrui et al., with the exception of containing an oxygen rather than a sulfur in the deoxyribose ring. While Weber does not specifically describe a compound anticipating the scope of present claim 1, the reference describes a number of specific compounds including compound 37 in p. 68:
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and compound 28 on p. 59:
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which differ from the compounds of present claim 1 only in that they lack the thiosugar group.
However, Gunaga et al. discloses that 4’-thionucleosides have the same configuration as 4’- oxonucleosides but have inherent advantages such as increased metabolic stability. (p. 2585 left column last paragraph) Various 2’- deoxy thionucleosides structures have been synthesized and developed as therapeutic agents (pp. 2496-2623, section 3) It would have been obvious to one of ordinary skill in the art at the time of the invention to make 4’- thionucleotide derivatives of compounds 9 and 12 of Ohrui et al. One of ordinary skill in the art would have seen the disclosure of Gunaga et al. as suggesting that this chemical modification is useful for improving the metabolic stability of nucleoside therapeutics including antiviral compounds, and furthermore that it has been successfully used in a variety of structurally similar compounds.
Regarding dependent claims 2, 3, 5, 8, 12-16, and 18, these claims are similarly obvious as they merely specify additional structural features or species previously described by Ohrui et al. as discussed above. Regarding dependent claims 20 and 22, which are directed to a pharmaceutical composition and method of treating HIV infection, Ohrui et al. describes administering the compound as part of a pharmaceutical composition, in a method of treating AIDS. (p. 4 second – fourth paragraphs) Regarding present claim 4, as discussed above, Ohrui et al. additionally discloses 5’- phosphate derivatives of these compounds.
For these reasons Weber in view of Gunaga et al. renders the claimed invention prima facie obvious.
Claims 6, 7, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Ohrui et al.in view of Gunaga et al. as applied to claims 1-5, 8, 12-16, 18, 20, and 21 above, and further in view of Mehellou et al. (Reference included with PTO-1449)
The disclosures of Ohrui et al. and Gunaga et al. are discussed above. Ohrui et al. in view of Gunaga et al. does not disclose a nucleoside having a phosphoarmidate at the 5’- position. (R2 in the present claims) However, Mehellou et al. discloses that nucleoside therapeutics including cancer therapeutics exert their biological activity by activation with nucleoside and nucleotide kinases inside the cell. (p. 2211 left column first paragraph) This process can be inefficient due to structural differences from native nucleosides, often leading to poor bioavailability. (p. 2211 left column second paragraph) Mehellou et al. further describes ProTide® derivatives of nucleoside drugs which include a monophosphate in which the anionic oxygen groups are masked. (p. 2212 right column second paragraph) These include aryloxy phosphoramidates. (p. 2213 table 1 stage 6, p. 2214 right column second paragraph) This prodrug modification has been applied to a wide spectrum of nucleoside drugs. (p. 2218 left column section 5) In one instance, Mehellou et al. discloses the clinical candidate GS-5734 (p. 2218 figure 10 compound 3) which has the same phosphoramidite moiety recited in present claim 19.
It would have been obvious to one of ordinary skill in the art at the time of the invention to make ProTide® phosphoramidite derivatives of the compounds described by Ohrui et al. in view of Gunaga et al. One of ordinary skill in the art would have seen Mehellou et al. as suggesting that this particular chemical modification is useful for applying to a wide variety of different nucleoside parent drugs including antitumor compounds.
Claims 21, 23, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Ohrui et al.in view of Gunaga et al. as applied to claims 1-5, 8, 12-16, 18, 20, and 21 above, and further in view of Blanco et al. (Reference included with PTO-892)
The disclosures of Ohrui et al. and Gunaga et al. are discussed above. Ohrui et al. in view of Gunaga et al. does not disclose a composition further comprising an additional therapeutic agent or a method further comprising administering an additional therapeutic agent. However, Blanco et al. discloses that inhibitors of HIV-1 integrase including dolutegravir are known to be effective for treating HIV infection. (p. 1313 first and second paragraphs)
It would have been obvious to one of ordinary skill in the art at the time of the invention to use an additional anti-HIV therapeutic agent such as an integrase inhibitor in the compositions and methods described by Ohrui et al. One of ordinary skill in the art would have been motivated to use both of these compounds together as they are seen to be useful for the same purpose of treating HIV infection.
Therefore the invention taken as a whole is prima facie obvious.
Conclusion
Claims 1-8, 12-16, and 18-24 are rejected. Claims 9-11 and 17 are objected to for depending from a rejected base claim but would be allowable if rewritten in independent form incorporating all the limitations of the rejected base claim and any intervening claims.
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/ANDREA OLSON/ Primary Examiner, Art Unit 1693 2/12/2026