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 .
Priority
The present application, filed December 20, 2023, is a national stage application of PCT/US2022/034603, filed June 22, 2022, and claims the benefit of U.S. provisional application 63/213513, filed June 22, 2021.
Status of the Application
Applicant’s preliminary amendment, received September 30, 2024, wherein claims 1, 3, 11, 21, 23, 25, 26, 29, 31, 33-36, 38, 58, 60, 61, 64, 66, 71, 74, 77, and 78 are amended and claims 2, 4-10, 12-20, 22, 24, 27, 28, 30, 32, 37, 39-57, 59, 62, 63, 65, 67, 72, 73, 75, and 76 are canceled, is acknowledged.
Claims 1, 3, 11, 21, 23, 25-26, 29, 31, 33-36, 38, 58, 60-61, 64, 66, 68-71, 74, and 77-78 are pending and examined on the merits herein.
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 58 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 58 makes reference to the specification for the claimed chemical compounds, rather than including the claimed chemical structures and/or chemical names in the claim. MPEP 2173.05(s) states: “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).”
Claim Rejections - 35 USC § 103
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 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.
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.
Claims 1, 3, 11, 21, 23, 25, 29, 33, 34, 35, 36, 58, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over Byun (U.S. Publication No. US 20220363708 A1; cited in PTO-892).
Byun was filed Mar. 19, 2021, and claims the benefit of U.S. provisional application 62/992,733, filed March 20, 2020. Therefore, Byun is eligible as prior art under 35 U.S.C. 102(a)(2).
Byun teaches prodrugs of 4'-C-substituted-2-halo-2'-deoxyadenoside nucleosides and their use in treating viral infections such as human immunodeficiency virus (cover page, Abstract, lines 1-5).
As one example compound, Byun teaches the compound shown below (p. 43, first compound). This compound has the structure as required by the compound of formula I with R1 as P(O)(OR3)(N(R4)(R5)) with R3 as phenyl with m as 0, R4 as hydrogen, and R5 as -C(R6)2-CO2R7 with R6 as hydrogen and C1 alkyl and R7 as C3 alkyl. This compound satisfies all limitations of claims 1, 3, 11, 21, 23, 25, 33, 34, 35, and 36, except for the requirement that R2 is chloro or hydrogen.
In addition, the stereochemistry of the phosphorus here is not indicated, but this compound has the same structure as either compound I-1 or I-2 (depending on the stereochemistry of the phosphorus) in Table 1 of the specification, except for the compound of Byun has R2 as fluoro, and the compounds I-1 and I-2 have R2 as chloro.
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As a second example, Byun teaches the compound shown below (p. 43, second compound). This compound has the structure as required by the compound of formula I with R1 as P(O)(OR3)(N(R4)(R5)) with R3 as phenyl with m as 0, R4 as hydrogen, and R5 as -C(R6)2-CO2R7 with R6 as hydrogen and C1 alkyl and R7 as C6 cycloalkyl. This compound satisfies all limitations of claims 1, 3, 11, 21, 23, 25, 33, 34, 35, and 36, except for the requirement that R2 is chloro or hydrogen.
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Byun further teaches that their disclosure provides a pharmaceutical composition comprising a compound of the present disclosure, and a pharmaceutically acceptable
Excipient (p. 46, [0221], lines 1-4).
Finally, Byun teaches the general formula of their compounds (p. 1, [0004]), indicating that variable X, which is in the same position as presently defined R2, may be halogen (p. 1, [0007]), and that halogen refers to bromo, chloro, fluoro, or iodo (p. 4, [0070]).
Byun does not teach a specific embodiment that satisfies all requirements of claim 1, specifically the identify of variable group R2.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the fluoro group in one of the compounds shown above with another halogen, such as chloro, bromo, or iodo. One of ordinary skill in the art would have been motivated to substitute the fluoro group in one of the compounds shown above with another halogen, such as chloro, bromo, or iodo because Byun discloses the above compounds as prodrugs of 4'-C-substituted-2-halo-2'-deoxyadenoside nucleosides, teaches their use in treating viral infections such as human immunodeficiency virus, and further teaches in their general structure that the fluoro position may be fluoro, chloro, bromo, or iodo. Accordingly, one of ordinary skill in the art would have contemplated derivatives of these compounds with chloro, bromo, or iodo in place of fluoro, because said compounds may also be effective for treating viral infections.
Regarding claim 25, which requires R3 is phenyl substituted with m instances of R8, and claim 29, which requires R8 represents independently for each occurrence halo, because m is permitted to be 0 in claim 23, the compounds above, which have unsubstituted phenyl, satisfy the limitations of claim 25. In addition, because claim 29 further limits R8, which is not present in the above compounds because m is 0, and claim 29 is also obvious over Byun.
Regarding claim 58, as stated, the stereochemistry of the phosphorus in the first compound above is not indicated. However, this compound has the same structure as either compound I-1 or I-2 (depending on the stereochemistry of the phosphorus) in Table 1 of the specification, except for the compound of Byun has R2 as fluoro, and the compounds I-1 and I-2 have R2 as chloro. Compound I-1 or I-2 would also be obvious over Byun for the same reasons described above. Regarding the stereochemistry of the phosphorus, because Byun describes the phosphorus stereochemistry in other embodiments, such as the second compound shown above, one of ordinary skill in the art would have contemplated derivatives with each phosphorus stereochemistry.
Therefore the invention taken as a whole is prima facie obvious.
Claims 61 and 71 are rejected under 35 U.S.C. 103 as being unpatentable over Byun (U.S. Publication No. US 20220363708 A1; cited in PTO-892) in view of Mehellou (Mehellou, Y.; et al. Journal of Medicinal Chemistry 2018, vol. 61, p. 2211-2226; cited in PTO-892), Markowitz (Markowitz, M.; et al. Current Opinion HIV and AIDS 2018, vol. 13, pp. 294-299; cited in PTO-892), and Satlin (Publication no. US 20240285664 A1; cited in PTO-892).
The U.S. application associated with Satlin, 18/566,413, was filed December 1, 2023, and is a national stage application of PCT/US2022/032120, filed June 3, 2022. It claims the benefit of U.S. provisional application 63/197,015, filed June 4, 2021. The embodiments of Satlin cited in this rejection are supported by 63/197,015 (see [0001], [0088], and [0231]-[0232] of the specification of 63/197,015). Therefore, Satlin is eligible as prior art under 35 U.S.C. 102(a)(2).
Byun teaches as described in the above rejection under 35 U.S.C. § 103. Specifically, Byun teaches the compound shown below (p. 43, first compound).
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Byun does not teach a method of treating a disorder selected from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, and an immune disorder other than a viral infection by administering a therapeutically effective amount of a compound of Formula I*, as defined by claim 61.
Mehellou teaches that the ProTide technology is a prodrug approach developed for the efficient intracellular delivery of nucleoside analogue monophosphates and monophosphonates (p. 2211, Abstract, liens 1-3). Mehellou teaches that ProTides are prepared such that a nucleoside analogue has the structure shown below, with the 5’-phosphoryl group derivatized with an aryl group and with a phosphonate ester (p. 2215, Figure 4).
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Mehellou further teaches that ProTide prodrugs are metabolized to release the nucleoside analogue as free monophosphate via the mechanism shown (p. 2216, Figure 6).
Finally, Mehellou teaches exemplary ProTide prodrugs, including Sofosbuvir (p. 2212, Figure 3; structure shown below). The phosphonate group in Sofosbuvir includes the same substituents as the prodrug taught by Byun and shown above.
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Therefore, in view of Mehellou, one of ordinary skill in the art would have recognized the compounds of Byun shown above as ProTide prodrugs that are converted to the corresponding 5’-monophosphate nucleoside analog.
Markowitz teaches the activity of EFdA (4’-ethynyl-2-fluoro-2’-deoxyadenosine) as an HIV-1 reverse transcriptase translocation inhibitor (document p. 1, Title). Markowitz teaches the structure of EFdA, as shown below (document p. 11, Figure 1).
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Finally, Markowitz teaches the active metabolite is EFdA-triphosphate (EFdA-TP) (p. 2, EFdA: Structure and Function section, third paragraph, lines 5-6).
Therefore, in view of Mehellou and Markowitz, one of ordinary skill in the art would have recognized that the resulting drug from the prodrug compound taught by Byun, is EFdA-monophosphate, which can be subsequently converted to the active metabolite EFdA-TP. Accordingly, one of ordinary skill in the art would have recognized that the prodrugs disclosed by Byun are converted to the same active metabolite as EFdA, and accordingly, would be reasonably expected to be effective when administered for treating the same diseases as EFdA.
Satlin teaches methods of enhancing cognition, inhibiting cognitive decline, treating a cognitive deficit disorder, or treating Creutzfeldt-Jakob disease (CJD) in a subject in need thereof
comprising administering a LINE-1 inhibitor (cover page, Abstract, lines 1-5). Satlin teaches that in one embodiment, their disclosure provides a method of treating or preventing CJD in a subject in need thereof, the method comprising administering a therapeutically effective amount of a LINE-I inhibitor to the subject.
Satlin further teaches the LINE-1 inhibitor may be the compound islatravir, which is the same compound as EFdA (p. 13, [0100], see structure of EFdA as shown).
Finally, Satlin teaches an assay wherein inhibition of human LINE-1 inhibitor activity is evaluated using compounds that include islatravir (p. 23, [0247], Table 1). Satlin teaches that their results demonstrate that islatravir, censavudine, and compounds of Formulae I-ITT are surprisingly potent human LINE-1 reverse transcriptase inhibitors (p. 23, [0248], lines 1-4) (emphasis added).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer the prodrug taught by Byun for the purposes of treating a neurodegenerative disorder such as Creutzfeldt-Jacob disease. One of ordinary skill in the art would have been motivated to administer the prodrug taught by Byun for the purposes of treating a neurodegenerative disorder, such as Creutzfeldt-Jacob disease, because Byun teaches prodrugs of EFdA, which is also known as islatravir, and renders obvious a prodrug of a chloro derivative of EFdA, and because Satlin teaches administration of a LINE-1 inhibitor for the purposes of treating Creutzfeldt-Jacob disease, expressly suggesting islatravir as one such LINE-1 inhibitor. Accordingly, one of ordinary skill in the art would have reasonably considered administering the prodrug above taught by Byun, which is a prodrug of islatravir, for the purposes of treating the neurodegenerative disorder Creutzfeldt-Jacob disease.
Therefore the invention taken as a whole is prima facie obvious.
Claims 61, 64, and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Byun (U.S. Publication No. US 20220363708 A1; cited in PTO-892) in view of Mehellou (Mehellou, Y.; et al. Journal of Medicinal Chemistry 2018, vol. 61, p. 2211-2226; cited in PTO-892), Markowitz (Markowitz, M.; et al. Current Opinion HIV and AIDS 2018, vol. 13, pp. 294-299; cited in PTO-892), and Weber (Publication no. US 20230293526 A1; cited in PTO-892).
Weber claims priority to U.S. provisional application 63/082,207, filed September
23, 2020. The subject matter cited in the rejection below is fully supported by 63/082,207 (see for example, claims 1, 20, and 21). Therefore, Weber is eligible as prior art under 35 U.S.C. 102(a)(2).
Byun teaches as described in the above rejection under 35 U.S.C. § 103.
Byun does not teach a method of treating a disorder selected from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, and an immune disorder other than a viral infection by administering a therapeutically effective amount of a compound of Formula I*, as defined by claim 61.
Mehellou and Markowitz teach as described in the above rejection under 35 U.S.C. § 103.
Weber teaches and claims a method for treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of a compound shown, including the compound EFdA (p. 42, claim 1; EFdA shown on p. 42, right column, fourth structure). Weber further claims the cancer is breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer (p. 43, claim 4).
In addition, Weber teaches LINE-I plays an important role in individual genome variations through insertional mutagenesis and sequence transduction, which occasionally lead to genetic diseases and disorders. Weber teaches LINE- I is reactivated in certain cancers thus contributing to tumor genome dynamics (p. 1, [0003], lines 6-10). Weber teaches that LINE-I element codes for two proteins, ORF1 p and ORF2 p, which are essential for its mobility (p. 2, [0003], lines 11-12). Weber teaches LINE-I retrotransposition is a hallmark of cancer, and increased expression of LINE-1 promotes pathogenesis by damaging the host DNA via mutation insertions and altering gene expression and chromosomal rearrangements (p. 1, [0004], lines 1-8). Weber concludes by stating there is a need in the art for LINE-I inhibitors for use in treating cancer (p. 1, [0005]).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer a prodrug taught by or rendered obvious by Byun for the purposes of treating cancer, such as breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer. One of ordinary skill in the art would have been motivated to administer the prodrug taught by Byun for the purposes of treating cancer, such as breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, or ovarian cancer, because Weber teaches administering a therapeutically effective amount of EFdA for treating cancer, and because the compounds of Byun, obvious as prodrugs of EFdA in view of Mehellou and Markowitz, would reasonably be administered for treating the same diseases as EFdA. Therefore, one of ordinary skill in the art would have considered administering a prodrug taught by Byun compounds for treating breast cancer, colon cancer, lung cancer, pancreatic ductal cancer, prostate cancer, ovarian cancer, or head and neck cancer.
Regarding claim 74, because Weber teaches the effects of LINE-I retrotransposition is a hallmark of cancer and increased expression of LINE-1 promotes pathogenesis, and concludes that there is a need in the art for LINE-I inhibitors for use in treating cancer, one of ordinary skill in the art would have recognized cancers that may be treated by nucleoside analogues such as islatravir as exhibiting expression of the LINE-1 elements recited in claim 74.
Therefore the invention taken as a whole is prima facie obvious.
Claims 61, 66, and 68-70 are rejected under 35 U.S.C. 103 as being unpatentable over Byun (U.S. Publication No. US 20220363708 A1; cited in PTO-892) in view of Mehellou (Mehellou, Y.; et al. Journal of Medicinal Chemistry 2018, vol. 61, p. 2211-2226; cited in PTO-892), Markowitz (Markowitz, M.; et al. Current Opinion HIV and AIDS 2018, vol. 13, pp. 294-299; cited in PTO-892), and Sedivy (WO 2020154656 A1; cited in PTO-892).
Byun teaches as described in the above rejection under 35 U.S.C. § 103.
Byun does not teach a method of treating a disorder selected from the group consisting of cancer, an inflammatory disorder, a neurodegenerative disorder, and an immune disorder other than a viral infection by administering a therapeutically effective amount of a compound of Formula I*, as defined by claim 61.
Mehellou and Markowitz teach as described in the above rejection under 35 U.S.C. § 103.
Sedivy teaches their invention relates to a method for treating age-associated inflammation by administering a reverse transcriptase inhibitor (RTI) to a patient in need thereof (p. 1, [0001], lines 1-3).
Sedivy teaches that given cellular senescence is one of the major drivers of organismal aging and aging-associated diseases, the methods of their invention can be used to prevent
or treat disorders or diseases that have been associated with cellular senescence (p. 34, [0118], lines 1-3), and diseases that have been associated with cellular senescence include Alzheimer’s disease, Huntington’s disease, Aicardi Goutiere's syndrome, and osteoarthritis, among others (p. 34, [0119], lines 1-9).
Finally, Sedivy teaches NRTI drugs that may be used in their invention include EFdA (p. 33, [0115], line 8).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to administer the prodrug taught by Byun for the purposes of treating Alzheimer’s disease, Huntington’s disease, Aicardi Goutiere's syndrome, and osteoarthritis because Sedivy teaches reverse transcriptase inhibitors as treating age-associated inflammation, teaches EFdA as one such reverse transcriptase inhibitor that may be used in this method, and further suggests their methods may be used for treating diseases associated with cellular senescence including Alzheimer’s disease, Huntington’s disease, Aicardi Goutiere's syndrome, and osteoarthritis. Accordingly, in view of Sedivy, one of ordinary skill in the art would have contemplated administration of EFdA for treating Alzheimer’s disease, Huntington’s disease, Aicardi Goutiere's syndrome, and osteoarthritis. Because the compounds of Byun are prodrugs of EFdA, as obvious over Byun, Mehellou, and Markowitz and would reasonably be considered to treat the same diseases as EFdA, one of ordinary skill in the art would have considered administering the prodrug above taught by Byun compounds for treating diseases that may be treated by EFdA, including Alzheimer’s disease, Huntington’s disease, Aicardi Goutiere's syndrome, and osteoarthritis.
Therefore the invention taken as a whole is prima facie obvious.
Claim 77 is rejected under 35 U.S.C. 103 as being unpatentable over Byun (U.S. Publication No. US 20220363708 A1; cited in PTO-892) as applied to claims 1, 3, 11, 21, 23, 25, 29, 33, 34, 35, 36, 58, and 60 above, and further in view of Mehellou (Mehellou, Y.; et al. Journal of Medicinal Chemistry 2018, vol. 61, p. 2211-2226; cited in PTO-892), Markowitz (Markowitz, M.; et al. Current Opinion HIV and AIDS 2018, vol. 13, pp. 294-299; cited in PTO-892), Satlin (Publication no. US 20240285664 A1; cited in PTO-892), and Hazuda (Publication No. WO 2017139519 A1; cited in PTO-892).
Byun teaches as described in the above rejection under 35 U.S.C. § 103.
Byun does not teach a method of inhibiting LINE I reverse transcriptase activity,
comprising contacting a LINE I reverse transcriptase with an effective amount of a
compound of claim 1, as recited in claim 77.
Mehellou, Markowitz, and Satlin teach as described in the above rejection under 35 U.S.C. 103.
Hazuda teaches methods for inhibition of HIV reverse transcriptase (cover page, Abstract, lines 1-2). Hazuda teaches compounds EFdA and ECdA have the chemical structures shown below (p. 2, line 7).
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Hazuda teaches that both compounds are metabolized in cells to their active triphosphate anabolite which inhibits HIV reverse transcriptase. Hazuda teaches that in contrast to NsRTis and NtRTI's currently available for the treatment of HIV infection, which lack a 3'-OH group to block incorporation of incoming nucleotide, EFdA and ECdA retain a 3'-OH group and act as a chain terminator by preventing translocation of the primer:template in the reverse transcriptase (RT) active site and preventing binding of incoming deoxyribonucleotides triphosphates (dNTPs) (p. 2, lines 9-14). Therefore, in view of Hazuda, one of ordinary skill in the art would have recognized each of EFdA and ECdA as compounds that may be metabolized in cells to their active triphosphate anabolite, which inhibits HIV reverse transcriptase.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to contact a LINE I reverse transcriptase with an effective amount of a compound of claim 1, in order to inhibit the activity of said LINE I reverse transcriptase. One of ordinary skill in the art would have been motivated to contact a LINE I reverse transcriptase with an effective amount of a compound of claim 1, in order to inhibit the activity of said LINE I reverse transcriptase because Byun teaches prodrugs of EFdA, as described above, and further renders obvious a prodrug of ECdA. Moreover, in view of Hazuda, one of ordinary skill in the art would have recognized ECdA as having the same activity of EFdA, inhibiting HIV reverse transcriptase. Finally, because Satlin recognizes EFdA is a LINE 1 inhibitor and the benefits of LINE 1 inhibitors for treating diseases such as CJD, one of ordinary skill in the art would have recognized ECdA as a potential LINE 1 inhibitor and potential treatment for diseases such as CJD, in view of its structural similarity to EFdA and each compound’s activity against HIV reverse transcriptase. Accordingly, one of ordinary skill in the art would have considered contacting a LINE 1 reverse transcriptase with the prodrug of ECdA obvious over Byun the purposes of inhibiting LINE 1, for example, for treating a disease such as CJD.
Therefore the invention taken as a whole is prima facie obvious.
Claim 78 is rejected under 35 U.S.C. 103 as being unpatentable over Byun (U.S. Publication No. US 20220363708 A1; cited in PTO-892) as applied to claims 1, 3, 11, 21, 23, 25, 29, 33, 34, 35, 36, 58, and 60 above, and further in view of Mehellou (Mehellou, Y.; et al. Journal of Medicinal Chemistry 2018, vol. 61, p. 2211-2226; cited in PTO-892), Markowitz (Markowitz, M.; et al. Current Opinion HIV and AIDS 2018, vol. 13, pp. 294-299; cited in PTO-892), Hazuda (Publication No. WO 2017139519 A1; cited in PTO-892) and Tyagi (Tyagi, R.; et al. Retrovirology 2017, vol. 14, article 21; cited in PTO-892).
Byun teaches as described in the above rejection under 35 U.S.C. § 103.
Byun does not teach a method of inhibiting LINE I reverse transcriptase activity,
comprising contacting a LINE I reverse transcriptase with an effective amount of a
compound of claim 1, as recited in claim 77.
Mehellou, Markowitz, and Hazuda teach as described in the above rejection under 35 U.S.C. 103.
Tyagi teaches that human endogenous retroviruses (HERVs) are genomic sequences of retroviral origin which were believed to be integrated into germline chromosomes millions of years ago and account for nearly 8% of the human genome. Tyagi teaches that although these sequences are mostly defective and inactive, some of the HERVs may be activated under certain physiological and pathological conditions. Tyagi teaches that although no drugs are designed specifically targeting HERVs, there are a panel of antiretroviral drugs designed against the human immunodeficiency virus and approved by the Federal Drug Administration
(FDA) (p. 1, Abstract, Background section, lines 1-6) (emphasis added).
Tyagi teaches the effect of these antiretroviral drugs for inhibiting HERVs. Tyagi teaches that they determined the effects of nucleoside and non-nucleotide reverse transcriptase (RT) inhibitors on HERV-K by a product enhanced reverse transcription assay, and found that that all RT inhibitors could significantly inhibit HERV-K RT activity (p. 1, Abstract, Results section, lines 1-4; data shown in p. 4, Figure 2). Tyagi concludes by stating they identified several FDA approved antiretroviral drugs that can effectively inhibit HERV-K, and these antiretrovirals may open new prospects for studying HERV-K pathophysiology and potentially for exploring
treatment of diseases in which HERV-K has been implicated.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to contact a HERV-K reverse transcriptase with an effective amount of a compound of claim 1, in order to inhibit the activity of said HERV-K reverse transcriptase. One of ordinary skill in the art would have been motivated to contact a HERV-K reverse transcriptase with an effective amount of a compound of claim 1, in order to inhibit the activity of said HERV-K reverse transcriptase, because Byun teaches prodrugs of EFdA, as described above, and further renders obvious a prodrug of ECdA. Moreover, in view of Hazuda, one of ordinary skill in the art would have recognized ECdA as having the same activity of EFdA, inhibiting HIV reverse transcriptase. Finally, because Tyagi teaches the effect of reverse transcriptase inhibitors designed against the human immunodeficiency virus on HERV-K RT, finding that all reverse transcriptase inhibitors tested could significantly inhibit HERV-K RT activity, one of ordinary skill in the art would have recognized that HIV reverse transcriptase inhibitors may be effective for inhibiting HERV-K reverse transcriptase activity.
In this instance, the rationale “obvious to try” would apply. Because Tyagi recognizes HIV reverse transcriptase inhibitors as effective for inhibiting HERV-K reverse transcriptase activity, and because Byun renders obvious prodrugs of compounds that are HIV reverse transcriptase inhibitors, as taught by Hazuda, one of ordinary skill in the art would have recognized the compounds obvious over Byun as a small number of identified HIV inhibitors that would reasonably be expected to inhibit the activity of HERV-K reverse transcriptase.
Therefore the invention taken as a whole is prima facie obvious.
Claims 26 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Byun (U.S. Publication No. US 20220363708 A1; cited in PTO-892) as applied to claims 1, 3, 11, 21, 23, 25, 29, 33, 34, 35, 36, 58, and 60 above, and further in view of Mehellou (Mehellou, Y.; et al. Journal of Medicinal Chemistry 2018, vol. 61, p. 2211-2226; cited in PTO-892) and Siddiqui (Siddiqui, A. Q.; et al. Journal of Medicinal Chemistry 1999, vol. 42, pp. 393-399; cited in PTO-892).
Byun teaches as described in the above rejections under 35 U.S.C. § 103.
Byun does not teach the compound of claim 23, wherein R3 is
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, as required by claim 26.
Mehellou teaches as described in the above rejections under 35 U.S.C. § 103.
Siddiqui teaches new substituted-aryl phosphoramidate derivatives of the anti-HIV drug d4T as membrane-soluble intracellular prodrugs (p. 393, Abstract, lines 1-2). Siddiqui teaches derivatives of compound 8 (see p. 393, Chart 1), that include a variety of phenyl substituents in the para position, as required by claim 26 (p. 395, Table 1). Siddiqui teaches the antiviral potency of these derivatives is correlated with their partition coefficient, with compound 8e, substituted with a para-chloro substituent, as the compound with the lowest EC50 value (p. 396, Figure 1). Siddiqui suggests this effect may reflect an increased membrane transport by passive diffusion for compounds bearing lipophilic substituents, and may also reflect an increased preference by cellular hydrolytic enzymes (p. 395, right column, first full paragraph, lines 25-29).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the aryl group in the compound obvious over Byun with a substituent, such as the p-chloro substituent taught by Siddiqui. One of ordinary skill in the art would have been motivated to substitute the aryl group in the compound obvious over Byun with a substituent, such as such as the p-chloro substituent taught by Siddiqui, because Mehellou teaches a method of preparing ProTide prodrugs of nucleoside analogs, and thus one of ordinary skill in the art would have recognized the prodrugs taught by Byun as prepared using the strategy taught by Mehellou, and because Siddiqui teaches that aryl substituents, such as the para-chloro substituent, shows improved properties on analogous nucleoside analog prodrugs.
In this instance, the rationale “use of a known technique to improve similar products in the same way” would apply. Because Siddiqui recognizes that nucleoside analogues with the same phosphoramidite prodrug moiety bearing substituents that increase lipophilicity show increased biological activity, one of ordinary skill in the art would have considered modifying the compounds obvious over Byun with similar substituents that increase lipophilicity, because said substituents may also increase the activity of the compounds obvious over Byun.
Therefore the invention taken as a whole is prima facie obvious.
Claims 1, 3, 11, 21, 23, 25, 29, 33-36, and 58 are rejected under 35 U.S.C. 103 as being unpatentable over Hazuda (Publication No. WO 2017139519 A1; cited in PTO-892) in view of Perrone (Perrone, P.; et al. Journal of Medicinal Chemistry 2007, vol. 50, p. 5463-5470; cited in PTO-892).
Hazuda teaches methods for inhibition of HIV reverse transcriptase (cover page, Abstract, lines 1-2). Hazuda teaches compounds EFdA and ECdA have the following chemical structures, as shown below (p. 2, line 7).
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Hazuda teaches that both compounds are metabolized in cells to their active triphosphate anabolite which inhibits HIV reverse transcriptase. Hazuda teaches that in contrast to NsRTis and NtRTI's currently available for the treatment of HIV infection, which lack a 3'-OH group to block incorporation of incoming nucleotide, EFdA and ECdA retain a 3'-OH group and act as a chain terminator by preventing translocation of the primer:template in the reverse transcriptase (RT) active site and preventing binding of incoming deoxyribonucleotides triphosphates (dNTPs) (p. 2, lines 9-14). Therefore, in view of Hazuda, one of ordinary skill in the art would have recognized each of EFdA and ECdA as a compound that may be used for inhibition of HIV reverse transcriptase, is metabolized in cells to the active triphosphate anabolite, which then inhibits HIV transcriptase.
Hazuda does not teach a compound of claim 1, with variable group R1 as the required phosphoramidate group.
Perrone teaches the synthesis of the anti-HCV agent 4’-azidoadenosine and the application of the phosphoramidate ProTide technology to this nucleoside (p. 5463, Abstract, lines 1-2).
Perrone teaches that modified nucleosides represent an important class of viral polymerase inhibitors. Perrone that nucleoside derivatives generally need to be phosphorylated to their corresponding triphosphate by host cell kinases to be converted to their corresponding pharmacologically active species (p. 5463, left column, Introduction section, fourth paragraph, lines 1-7). Perrone teaches, however, that in many cases, nucleoside analogues are poor substrates for nucleoside kinases, and that the dependence on phosphorylation for activation of a particular nucleoside may be a problem in cells where the nucleoside kinase activity is low or even lacking. Perrone teaches the pharmacologically active triphosphate species cannot be considered as a possible drug candidate because of high instability and poor cellular permeation, and for many nucleosides the first phosphorylation constitutes the rate-limiting step in the synthetic pathway to triphosphate formation, suggesting that monophosphate analogues might be useful antiviral agents. However, nucleoside monophosphates are also generally unstable in blood and show poor membrane permeation (p. 5463, Introduction section, paragraph bridging left and right columns, lines 1-13).
Perrone teaches that to bypass this first rate-limiting step required of nucleoside analogues, their group has developed the aryloxy-phosphoramidate (compound 2, shown on p. 5464, Figure 1), which permits bypass of the initial nucleoside kinase dependence, by the intracellular delivery of the monophosphorylated nucleoside analogue in the membrane permeable “Pro-Tide” form. Perrone teaches this technology increases the lipophilicity of
the nucleoside monophosphate analogues and the intracellular availability by passive diffusion and that this method has been applied to various nucleoside analogues including d4A, ddA, L-Cd4A, and d4T (p. 5463, right column, first full paragraph, lines 1-11). Perrone teaches that in these examples, the corresponding aryloxy-phosphoramidates have shown an enhancement in antiviral activity against target viruses such as HIV and HBV compared to the parent nucleoside analogues in vitro, and in contrast to the nucleoside analogues, the phosphoramidates retained full antiviral activity in kinase-deficient cell lines (p. 5463, right column, second full paragraph, lines 1-6).
As specific examples, Perrone teaches compounds 20 and 21, which have R as ethyl and Ar as 1-naphthyl or as phenyl (p. 5466, Scheme 4; example structure shown below). Perrone teaches that compounds 20 and 21 show improved anti-HCV activity compared with 4’-azidoadenosine (p. 5466, Table 2).
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to apply the ProTide prodrug methodology taught by Perrone for 4’-Azidoadenosine to the nucleoside analogue ECdA taught by Hazuda. One of ordinary skill in the art would have been motivated to apply the ProTide prodrug methodology taught by Perrone to the nucleoside analogue ECdA taught by Hazuda because Hazuda teaches ECdA for treating HIV, and because Perrone teaches a structurally related nucleoside analogue, 4’-Azidoadenosine, as having improved potency against HCV when converted into its corresponding prodrug. In addition, one of ordinary skill in the art would have recognized the general benefits of the ProTide methodology disclosed by Perrone, including the opportunity to bypass the first rate-limiting step of phosphorylation required of nucleoside analogues by intracellularly delivering the nucleoside analogue in the membrane permeable ProTide form, as beneficial for additional nucleoside analogues, including ECdA. Accordingly, because the conversion of a nucleotide analogue to the ProTide prodrug, as described by Perrone, is recognized as improving the activity of various nucleoside analogues, one of ordinary skill in the art would have contemplate the same ProTide prodrug approach for ECdA taught by Hazuda, because conversion of ECdA to the ProTide prodrugs may improve their activity for treating HIV.
Applying the ProTide prodrug approach taught by Perrone (e.g., as shown for compounds 20 and 21) to ECdA would produce a compound that satisfies the limitations of claims 1, 3, 11, 21, 23, 25, 26, 29, and 33-36, and would generate compound I-5 or I-36 of Table 1-A, depending on the stereochemistry of the phosphorus group, which is not defined by Perrone.
Therefore the invention taken as a whole is prima facie obvious.
Claim 31 is rejected under 35 U.S.C. 103 as being unpatentable over Hazuda (Publication No. WO 2017139519 A1; cited in PTO-892) in view of Perrone (Perrone, P.; et al. Journal of Medicinal Chemistry 2007, vol. 50, p. 5463-5470; cited in PTO-892) as applied to claims 1, 3, 11, 21, 23, 25, 29, 33-36, and 58 above, and further in view of Yan (Publication no. WO 2021202886 A1; cited in PTO-892).
The PCT application associated with the publication of Yan, PCT/US202l/025399, was filed April 1, 2021. Because Yan designates the US in box 81 of the publication, Yan is eligible as prior art under 35 U.S.C. § 102(a)(2).
Hazuda teaches as described in the above rejections under 35 U.S.C. § 103.
Hazuda does not teach the compound of claim 23, wherein R3 is hydrogen, as required by claim 31.
Perrone teaches as described in the above rejection under 35 U.S.C. § 103.
Yan teaches that inclusion of a phosphoramidate moiety has become an increasingly attractive pro-drug strategy for anionic phosphate- or phosphonate-containing drugs. Yan teaches that while the development of phosphoramidate and phosphonoamidate prodrugs has been primarily spearheaded by the antiviral nucleotide field, this approach is emerging as an appealing strategy for the delivery of novel phosphonate-containing cancer therapeutics (p. 1, [0002], lines 2-7).
Yan teaches that included in their invention is a method for reducing the risk of acquiring HIV (e.g., HIV-1 and/or HIV-2) comprising administering a compound of Formula I, optionally in combination with one or more other antiretroviral agents, to the patient (p. 28, [086], lines 1-3).
As one example, Yan teaches the synthesis of compound 26 (p. 41, see scheme above [0105]; structure shown below). This compound has the phosphoramidate substituent required by claim 31, with R3 as hydrogen, R4 as hydrogen, R5 as C(R6)2-CO2R7, wherein R6 is hydrogen and C1 alkyl, and R7 is C3 alkyl. However, this compound differs from the compound of claim 31 in that the nucleoside analog is not ECdA, but rather a different fluorinated adenosine derivative.
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to prepare a prodrug of ECdA, as taught by Hazuda, following the guidance of Yan. One of ordinary skill in the art would have been motivated to prepare a prodrug of ECdA, as taught by Hazuda, following the guidance of Yan, because Hazuda teaches the nucleoside analogue ECdA for treating viral infections, including HIV, and because Yan teaches prodrugs of nucleoside analogues that may be used for treating viral infections and other diseases, including HIV.
In this instance, the rationale “use of a known technique to improve similar products in the same way” would apply. Because Hazuda teaches the nucleoside analogue ECdA for the purposes of treating viral infections, and because Yan teaches a prodrug strategy and applies it to other nucleoside analogues, including those used for treating HIV, one of ordinary skill in the art would have contemplated applying said prodrug strategy to alternative HIV therapies, including ECdA, because such a prodrug may also show the improved therapeutic activity of the phosphoramidated prodrugs taught by Perrone.
Therefore the invention taken as a whole is prima facie obvious.
Claim 38 is rejected under 35 U.S.C. 103 as being unpatentable over Hazuda (Publication No. WO 2017139519 A1; cited in PTO-892) in view of Meppen (Meppen, M; et al. European Journal of Medicinal Chemistry 2009, vol. 44, pp. 3765-3770; cited in PTO-892).
Hazuda teaches as described in the above rejection under 35 U.S.C. § 103.
Hazuda does not teach a compound with a required cyclic phosphoramidate group recited in claim 38.
Meppen teaches cyclic phosphoramidates as prodrugs of 2’-C-methylcytidine (p. 3765, Title). Meppen teaches the RNA-dependent RNA polymerase (RdRp) is at the heart of
the viral replication complex, and that nucleoside as well as non-nucleoside inhibitors of this enzyme have been described (p. 3765, right column, second paragraph, lines 1-3). Meppen teaches the efficiency of NTP formation of a given nucleoside often rests on the rate-limiting first phosphorylation, which converts the nucleoside into its corresponding monophosphate anabolite by cellular kinases (p. 3765, right column, third paragraph, lines 1-4). Meppen teaches several strategies have been developed to address rate-limiting phosphorylation, such as, as one example, delivery of a masked nucleoside monophosphate (p. 3766, left column, lines 1-4).
Meppen teaches their development of prodrugs of the 2’-C-methylcytidine 4 via Protide approaches (p. 3766, left column, first paragraph, lines 1-2 and 8-13), and Meppen teaches that during their prodrug development, they designed cyclic phosphoramidates as shown in structure 3 (p. 3766, Figure 1). Meppen teaches that these structures have two potential advantages over Protide prodrugs: 1) the cyclisation reduces the degree of rotational freedom as compared to generally described Protide prodrugs, possibly allowing for improved entry into the
cell, and 2) less phenol related cytotoxic side effects might occur (p. 3766, right column, lines 1-6). As exemplary cyclic prodrugs, Meppen teaches compound 9 S.E. (p. 3767, Scheme 3; structure shown below). This compound has a 3’,5’ cyclic phosphate with presently defined R1 as N(R4)(R5), with R4 as hydrogen and R5 as C(R6)2-CO2(R7), with R6 as hydrogen and as C1 alkyl and with R7 as C2 alkyl.
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It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to prepare a 3’,5’-cyclic phosphoramidate prodrug, as taught by Meppen, of the nucleoside analogue EFdA or ECdA taught by Hazuda. One of ordinary skill in the art would have been motivated to prepare a 3’,5’-cyclic phosphoramidate prodrug, as taught by Meppen, of EFdA or ECdA, because Hazuda recognizes EFdA and ECdA as antiviral agents, and because Meppen teaches potential advantages of their cyclic phosphoramidate prodrug strategy compared with other prodrug strategies such as the ProTide strategy, including potential improved entry into the cell and fewer phenol-related cytotoxic side effects. Accordingly, one of ordinary skill in the art would have considered applying the prodrug strategy disclosed by Meppen to EFdA or ECdA, a nucleoside analogue recognized for treating HIV, because said prodrug strategy may offer the benefits described by Meppen, including improved entry into the cell and fewer phenol-related cytotoxic side effects, compared with other prodrug strategies.
In this instance, the rationale “use of a known technique to improve similar products in the same way” would apply. Because Hazuda recognizes EFdA and ECdA for treating viral infections, and Meppen teaches a prodrug strategy for nucleoside analogues that offers potential advantages compared with the ProTide strategy, one of ordinary skill in the art would have contemplated applying this method taught by Meppen to the compounds disclosed by Hazuda.
Therefore the invention taken as a whole is prima facie obvious.
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, 3, 11, 21, 23, 25, 29, 33-36, 58, 60, 61, 64, 66, 68-71, 74, and 77-78 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, and 13-21 of co-pending U.S. patent application 18/846085 (reference application, hereinafter ‘085; corresponding pre-grant publication US 20250186475 A1 cited in PTO-892) in view of Perrone (Perrone, P.; et al. Journal of Medicinal Chemistry 2007, vol. 50, p. 5463-5470; cited in PTO-892).
The amended claims of ‘085 received May 30, 2025 are cited in this provisional nonstatutory double patenting rejection.
The present application and ‘085 are each assigned to Rome Therapeutics, Inc. and include Donna Romero and Dennis Zaller as inventors.
Claim 1 of ‘085 claims a method of treating a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I to treat the disorder; wherein Formula I is represented by:
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wherein R1 is hydrogen, -P(O)(OH)2, -P(O)(OH)-O-P(O)(OH)2, or -(P(O)(OH))2-O-P(O)(OH)2; and R2 is fluoro or chloro.
Claim 2 of ‘085 depends from claim 1 and requires the compound of Formula I is administered in a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, adjuvant, and/or vehicle.
Claim 13 of ‘085 claims the method of claim 1, wherein the compound is as shown, wherein R1 is hydrogen and R2 is chloro.
Claim 14 ‘085 claims the disorder is cancer, and claim 15 claims the cancer is selected from the group that includes for example, breast cancer.
Claim 16 of ‘085 claims the disorder is an autoimmune disorder, claim 17 claims the autoimmune disorder is selected from a group that includes, for example, rheumatoid arthritis.
Claim 18 of ‘085 claims the disorder is a neurological disorder, and claim 19 claims the disorder is selected from a group that includes, for example, Alzheimer's disease.
Claim 20 of ‘085 depends from claim 1 and requires the subject has (i) elevated expression of LINEl RNA, LINEl ORFl polypeptide, and/or LINEl ORF2 polypeptide; and/or (ii) elevated activity of LINEl reverse transcriptase, and claim 21 claims the subject has (i) expression of HERV-K RNA and/or (ii) activity of HERV-K reverse transcriptase.
Claim 3 of ‘085 claims a method of inhibiting LINEl reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder, comprising contacting a LINEl reverse transcriptase with an effective amount of a compound of Formula I, in order to inhibit the activity of said LINE l reverse transcriptase; wherein Formula I is represented by the compound as shown in the claim, which is the same compound recited in claim 1 of ‘085.
Claim 6 of ‘085 claims a method of inhibiting HERV-K reverse transcriptase activity in a subject suffering from a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder, comprising contacting a HERV-K reverse transcriptase with an effective amount of a compound of Formula I, in order to inhibit the activity of said HERV-K reverse transcriptase; wherein Formula I is represented by the compound as shown in the claim, which is the same compound recited in claim 1 of ‘085.
The claims of ‘085 do not claim the compound represented by Formula I of claim 1, specifically with respect to variable group R1.
Perrone teaches as described in the above rejections under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to apply the ProTide methodology taught by Perrone to the compounds recited in claims 1 and 13 of ‘085, in view of the claims of ‘085 claiming the compounds recited in claims 1 and 13 for use in the methods of claims 1 and 13-21, and in view of Perrone teaching a structurally related agent, 4’-Azidoadenosine, as having improved potency against HCV when converted into its corresponding prodrug. In addition, in view of the general benefits of the ProTide methodology disclosed by Perrone, including the opportunity to bypass the first rate-limiting step of phosphorylation required of nucleoside analogues by intracellularly delivering the nucleoside analogue in the membrane permeable ProTide form. Accordingly, because the conversion of a nucleotide analogue to the ProTide prodrug, as described by Perrone, is recognized as improving the activity of various nucleoside analogues, one of ordinary skill in the art would have contemplate the same ProTide prodrug approach of the compounds claimed by ‘085, because conversion of these compounds to the ProTide prodrugs may improve their activity in treating the claimed diseases.
Applying the ProTide prodrug approach to the compounds required by the methods claimed by ‘085 would produce a compound that satisfies the limitations of claims 1, 3, 11, 21, 23, 25, 26, 29, and 33-36, a composition that satisfies the limitations of claim 60, and a method that satisfies the limitations of claims 64, 66, 68-71, 74, and 77-78.
This is a provisional double patenting rejection because the patentably indistinct claims have not been patented.
Claim 26 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, and 13-21 of co-pending U.S. patent application 18/846085 (reference application, hereinafter ‘085) in view of Perrone (Perrone, P.; et al. Journal of Medicinal Chemistry 2007, vol. 50, p. 5463-5470; cited in PTO-892) as applied to claims 1, 3, 11, 21, 23, 25, 29, 33-36, 58, 60, 61, 64, 66, 68-71, 74, and 77-78 above, and further in view of Siddiqui (Siddiqui, A. Q.; et al. Journal of Medicinal Chemistry 1999, vol. 42, pp. 393-399; cited in PTO-892).
The claims of ‘085 claim as described in the above provisional nonstatutory double patenting rejection.
The claims of ‘085 do not claim a compound with variable group R3 is as shown in claim 26.
Perrone teaches as described in the above rejection under 35 U.S.C. § 103 and the above nonstatutory double patenting rejection.
Siddiqui teaches as described in the above rejection under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to modify variable group R3 in the compounds, obvious over the claims of ‘085 in view of Perrone, to include substituent R8 as required by claim 26, because Siddiqui teaches that aryl substituents on aryl phosphoramidite prodrugs can, in some instances, improve the activity of a prodrug therapeutic. Accordingly, one of ordinary skill in the art would have considered modifying the prodrugs obvious over the claims of ‘085 in view of Perrone with an aryl group substituent, such as the lipophilic para-chloro substituent taught by Siddiqui, because said substituent showed the most beneficial effect of the substituents evaluated by Siddiqui.
This is a provisional double patenting rejection because the patentably indistinct claims have not been patented.
Claim 31 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, and 13-21 of co-pending U.S. patent application 18/846085 (reference application, hereinafter ‘085) in view of Perrone (Perrone, P.; et al. Journal of Medicinal Chemistry 2007, vol. 50, p. 5463-5470; cited in PTO-892) as applied to claims 1, 3, 11, 21, 23, 25, 29, 33-36, 58, 60, 61, 64, 66, 68-71, 74, and 77-78 above, and further in view of Yan (Publication no. WO 2021202886 A1; cited in PTO-892).
The claims of ‘085 claim as described in the above nonstatutory double patenting rejection.
The claims of ‘085 do not claim a compound with R3 as hydrogen as required by present claim 31.
Perrone teaches as described in the above nonstatutory double patenting rejection.
Yan teaches as described in the above rejection under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to prepare a compound claimed by ‘085 as a phosphoramidated prodrug, in view of ‘085 claiming these compounds for the purposes of treating several different diseases and conditions, Perrone teaching the improved availability of phosphoramidated prodrugs, and Yan teaching exemplary phosphoramidated prodrugs of nucleoside analogues that include R3 as H. Accordingly, one of ordinary skill in the art would have contemplated a prodrug as taught by Yan based on a nucleoside analogue claimed by ‘085, such as the compound recited in claim 13, because such a prodrug may also show the improved therapeutic activity of the phosphoramidated prodrugs taught by Perrone.
This is a provisional double patenting rejection because the patentably indistinct claims have not been patented.
Claim 38 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, and 13-21 of co-pending U.S. patent application 18/846085 (reference application, hereinafter ‘085) in view of Meppen (Meppen, M; et al. European Journal of Medicinal Chemistry 2009, vol. 44, pp. 3765-3770; cited in PTO-892).
The claims of ‘085 claim as described in the above nonstatutory double patenting rejections.
The claims of ‘085 do not claim a compound that satisfies the requirements of present claim 38.
Meppen teaches as described in the above rejection under 35 U.S.C. § 103.
It would therefore have been prima facie obvious to one of ordinary skill in the art to prepare a cyclic phosphoramidate prodrug, as taught by Meppen, of a compound claimed by ‘085, such as the compound of claims 12 or 13, because Meppen teaches potential advantages of their cyclic phosphoramidate prodrug strategy compared with other prodrug strategies such as the ProTide strategy, including potential improved entry into the cell and fewer phenol-related cytotoxic side effects, and accordingly, one of ordinary skill in the art would have contemplated the prodrugs taught by Meppen, because said prodrugs may be more effective therapeutics when practicing the methods claimed by ‘085.
In this instance, the rationale “use of a known technique to improve similar products in the same way” would apply. Because the claims of ‘085 recognize the compounds of claims 12 ad 13 has having therapeutic activity, and because Meppen teaches a prodrug strategy that may improve the activity of nucleoside analogues and offers potential advantages compared with the ProTide strategy, one of ordinary skill in the art would have contemplated applying this method taught by Meppen to the compounds recited in the claims of ‘085.
This is a provisional double patenting rejection because the patentably indistinct claims have not been patented.
Conclusion
No claims are allowed.
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/B.M.B./ Examiner, Art Unit 1693
/ANDREA OLSON/ Primary Examiner, Art Unit 1693
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