DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Application
Receipt is acknowledged of Applicants’ preliminary amendment, filed on 07/13/2026, in which claims 12 and 20 are amended and claims 13 and 17 are cancelled.
Claims 1-12, 14-16, 18-20 are pending.
Priority
The instant application is a 371 of PCT/P2022/074740 filed on 09/06/2022, which claims foreign priority to EP 21195043.1, filed on 09/06/2021.
Election/Restrictions
Applicant’s election of Group II, drawn to a compound of general formula (II), encompassing claims 12-20 in the reply filed on 07/13/2026 is acknowledged. Election was made without traverse in the reply filed on 07/13/2026. Similarly, Applicant’s election of a compound of general formula (II) wherein o1 is OH, o3 is H, M is O, X1 is H, X2 is TIPS, h is Br, R1 and R2 together form -CH=C(ar)-, and ar is phenyl readable on claims 14 and 15 in the reply filed on 07/13/2026 is acknowledged. For purposes of compact prosecution, the species election is withdrawn.
Claims 1-11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/13/2026 .
Claims 12, 14-16, and 18-20 are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) dated 02/29/2024 and 07/13/2026 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Objections
Claim 20 is objected to because of the following informalities: claim 20 recites the phrase “wherein X1 is and X2 together form” (emphasis added) on line 4. This is an obvious typographical error and should be corrected to “wherein X1 and X2 together form”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 12, 14-16, and 18-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 on line 4 recites “h is H, halogen, or Q;”. However, claim 12 does not define the scope of Q, and thus the scope of h is unclear. For purposes of compact prosecution, the claim will be interpreted as a compound of general formula (II) in which h is H or halogen.
Claims 14 and 15 on line 3 each recite “X2 is p′”. However, claims 14 and 15 on line 4 each recite “p′ is preferably TIPS”. The phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. For purposes of compact prosecution, the claim will be interpreted as requiring that X2 is TIPS, as the instant claims define X2 as p′ and the only recitation to provide the scope of p′ is that “p′ is preferably TIPS”.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 20 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 20 depends on claim 12 and therefore include the limitations of claim 12. Claim 20 provides a limitation which recites a compound to be excluded from the genus of claim 12. This compound to be excluded is described as a compound in which “X1 is and X2 together form an acetonide protecting group”. However, claim 12 recites “X1 and X2 are each independently chosen from H or in each instance independently chosen from a hydroxyl protective group”. Thus the scope of the genus of claim 12 does not include compounds in which X1 and X2 together form an acetonide protecting group and thus the limitations of claim 20 fails to further limit the genus of claim 12.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 12 and 20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Gosh et al. (Bioorganic & Medicinal Chemistry Letters, 2005; PTO-892).
Gosh discloses a library of 7-methyl guanosine nucleoside and nucleotide analogs (abstract). Gosh recites compound 13 in Scheme 1 on page 2178, shown below.
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This is the sodium salt of a compound of general formula (II) in which h is H, X1 and X2 are both H, R1 and R2 are both H, o1 is OH, and M is O.
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.
Claims 12 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Gosh et al. (Bioorganic & Medicinal Chemistry Letters, 2005; PTO-892) in view of Głowacka et al. (Molecules, 2015; PTO-892).
Gosh discloses a library of 7-methyl guanosine nucleoside and nucleotide analogs (abstract). Gosh recites compound 13 in Scheme 1 on page 2178, shown below.
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This is the sodium salt of a compound of general formula (II) in which h is H, X1 and X2 are both H, R1 and R2 are both H, o1 is OH, and M is O.
The teachings of Gosh differ from that of the instantly claimed invention in that Gosh does not teach a crystalline compound.
Głowacka discloses the synthesis of a series of alkylphosphonates as acyclic analogues of guanosine and their antiviral activity (abstract). All final compounds were purified by chromatography and solids were finally recrystallized (paragraph bridging pages 18792-18793). These include the phosphonate guanosine derivatives 16a, 16d, 16e, 16f, 16g, 16h, and 16j (experimental section beginning on page 18795), which are shown in general formula in Scheme 3 on page 18793.
It would have been prima facie obvious to combine the teachings of Gosh and Głowacka before the effective filing date of the claimed invention by recrystallizing the compounds of Gosh as described in Głowacka to arrive at the instantly claimed invention. It would have been prima facie obvious for one of ordinary skill in the art to recrystallize the compounds of Gosh because Głowacka teaches and suggests recrystallization as a method of purifying phosphonate guanosine derivatives. One of ordinary skill in the art would have a reasonable expectation of success because both Gosh and Głowacka teach the synthesis of phosphonate guanosine derivatives.
Allowable Subject Matter
Claims 14-15 and 18-19 contain allowable subject matter. The following is a statement of reasons for the indication of allowable subject matter.
Claims 14-15 and 18-19 are drawn to a compound of general formula (II), wherein o1 is OH, o3 is H, M is S or O, X1 is H, X2 is TIPS, h is Br, R1 and R2 together form -CH=C(ar)-, and ar is phenyl in claims 14 and 18 or 4-methylphenyl in claims 15 and 19.
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Thus the instantly claimed invention requires an 8-Br-PET nucleoside that is a 5’ H-phosphonate monoester, 3’ unprotected, and 2’ silyl protected.
The closest prior art is Genieser et al. (US5625056A; PTO-892), which discloses new derivatives of Sr and Rr configured cyclic guanosine-3',5'-phosphorothioates which are cell membrane permeable inhibitors (Rp-isomers) and stimulators (Sp-isomers) of cyclic GMP-dependent protein kinase (abstract). Genieser specifically discloses Rp-8-Br-PET-cGMPS, which is a competitive inhibitor of cGMP-dependent protein kinases, and has an inhibition constant of Ki 0.03 μM (col. 8, lines 65-67). Rp-8-Br-PET-cGMPS selectively blocks the cGMP signal transduction pathway without affecting cAMP-mediated effects and as an inhibitor at thrombocyte membranes it surpasses the effectivity Rp-8-pCPT-cGMPS by a factor of 5-10 (col. 9, lines 1-9). Genieser discloses Rp-8-Br-PET-cGMPS as a compound of formula I, which is shown below, in which X is Br, and R5 is H.
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Genieser teaches that, in order to further enhance the membrane permeability of the compounds, it is advantageous to modify the 2'-hydroxyl group of the pentose group with hydrophobic groups, which after penetration of the cellular membrane can be cleaved again, hydrolytically, by intracellular enzymes (col 4, lines 41-46). An example for groups that can be cleaved hydrolytically from the 2'-hydroxyl group are silyl groups. Especially suitable are trialkylsilyl groups, in particular the trimethyl silyl groups having linear or branched C1-C5 alkyl substituents (col 4, lines 51-55). Genieser discloses that in formula I, R5 may be hydrogen, a (tri)alkylsilyl or an acyl group (claim 1), and that R5 may be trimethylsilyl (claim 11).
The teachings of Genieser would have provided one of ordinary skill in the art with the motivation to substitute the R5 hydrogen of the Rp-8-Br-PET-cGMPS of Genieser with a (tri)alkylsilyl group such as a trimethylsilyl group, because Genieser teaches that it is advantageous to modify the 2'-hydroxyl group with hydrophobic groups to further enhance the membrane permeability of the compounds. Thus the teachings of Genieser would have suggested a Rp-8-Br-PET-cGMPS that is 2’ silyl protected.
However, neither the teachings of Genieser nor the prior art more broadly suggest a 2’ silyl protected 8-Br-PET nucleoside that is a 5’ H-phosphonate monoester and 3’ unprotected. The teachings of the prior art disclose 8-Br-PET nucleosides specifically as precursors for 8-Br-PET-cGMP analogues, which act on cyclic GMP-dependent protein kinases. The synthesis of cGMP analogues is not taught to proceed through an 8-Br-PET nucleoside 5’ H-phosphonate monoester which is 3’ unprotected. For example, rather than teaching a 5’ H-phosphonate monoester in which the 8-Br-PET group is already installed, Genieser teaches the synthesis as starting from Rp-8-bromoguanosine-3',5'monophosphorothioate which is subsequently modified with 2-boromoacetophenone to reach the 8-Br-PET comprising compound.
Thus one of ordinary skill in the art would not have been motivated to synthesize a 5’ H-phosphonate monoester of an 8-Br-PET nucleoside that is 3’ unprotected and 2’ silyl protected, and claims 14-15 and 18-19 are not obvious over the prior art.
Conclusion
No claims are allowed.
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/S.G.H./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693
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