DETAILED ACTION
The present application is a national stage entry of PCT/CN2022/073159, filed 21 January 2022, and claims foreign priority to CN202210064310.4, filed 20 January 2022 and CN202110094088.8, filed 22 January 2021.
The preliminary amendment filed 27 January 2026 is acknowledged. Claims 1 and 4-14 are pending in the current application. Claims 11 and 12 are withdrawn as being drawn to a non-elected invention, see below. Claims 1, 4-10, 13 and 14 are examined on the merits herein.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-7 in the reply filed on 27 January 2026 is acknowledged.
During a telephone conversation with Kyler Rose on 27 January 2026 a provisional election was made without traverse to prosecute the species of the first compound in the Table provided in the remarks on 27 January 2026. Affirmation of this election must be made by applicant in replying to this Office action. Claims 11 and 12 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claims 11 and 12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 27 January 2026.
The species was searched, and found to be free of the prior art. The species was expanded to include both compounds recited in present claim 1, and also found to be free of the prior art.
Closest Prior Art
Ciulli et al. (WO 2016/146985, cited in IDS submitted 18 December 2023) is concerned with preparing conjugates having an E3 ubiquitin ligase protein binding ligand, having utility in proteolysis targeted chimeras (PROTAC), (abstract). The compounds of Ciulli et al. are particularly drawn towards conjugates that bind to a protein within the bromo- and Extra-terminal (BET) family of proteins for the treatment of proliferative, autoimmune or inflammatory diseases (abstract).
The compounds of Ciulli et al. have the structure A-L-B, where A is an E3 ubiquitin ligase protein binding ligand of formula I, with VHL-1 and VHL-2 s preferred species of A:
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(Fig. 1). The following is an exemplary linker:
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, which is combined with JQ1 (as ligand B) to give the following conjugate:
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(fig. 1b). According to claim 40, the target protein B can include a hepatitis B reverse transcriptase. The list of target proteins in claim 40 includes over 100 broad classes.
Huang et al. (Fudan Univ. J. Med. Sci., 2013, vol. 40, no. 2, pp.233-238, cited in IDS submitted 18 December 2023) teach nucleoside analogs that are effective antiviral treatments towards hepatitis B infections include entecavir (ETC), lamivudine (LAM), adefovir dipovoxil (ADV), telbivudine (TEB) and tenofovir disoproxil fumarate (TDF), (abstract). These compounds inhibit DNA polymerase and reverse transcriptase of the virus (p.2, last para).
From the large list of possible target proteins, there is no motivation to select where the target protein is hepatis B reverse transcriptase from the list of over 100 classes of protein targets. Furthermore, there is no motivation to select entecavir as the compound that targets hepatitis B reverse transcriptase from the list of over 100 classes of protein targets, particularly where each class encompasses many compounds that target those proteins, let alone conjugate it to the claimed E3 ubiquitin ligase protein binding ligand via the linkers presently claimed without hindsight.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 10 and 14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a viral infection caused by hepatitis B, does not reasonably provide enablement for treating, preventing or diagnosing various diseases related to DNA polymerase. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The Applicant’s attention is drawn to In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) The nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
The nature of the invention: The nature of the invention is the preparation of bifunctional, PROTAC compounds, which has a ligand for binding a DNA polymerase and a ligand for binding E3 ubiquitin ligase. The claims are drawn towards entecavir as the ligand for binding hepatitis B DNA polymerase.
The breadth of the claims: The breadth of the claims includes degrading and inhibiting any DNA polymerase, and treating, preventing or diagnosing any disease related to any DNA polymerase. Thus, the breadth of the claims includes situations where the subject has not even been exposed to hepatitis B.
The state of the prior art:
Prevent is defined as “keep from happening or arising; make impossible”. See provided definition of prevent (definition of prevent, WordNet, cited in PTO-892). There is no prior art disclosing making hepatitis B infections impossible by administering an entecavir conjugate.
Huang et al. (Fudan Univ. J. Med. Sci., 2013, vol. 40, no. 2, pp.233-238, cited in IDS submitted 18 December 2023) teach Entecavir is approved by the FDA in 2005 for the treatment of HBV infections. Huang et al. teach the compound is a cyclopentyl guanosine analogue, that competes with deoxyguanosine triphosphate (p.4). Entecavir inhibits all three activities of HBV polymerase: the initiation of HBV polymerase, the formation of negative strand of pregenomic RNA reverse transcription and the synthesis of positive strand of HBV DNA (p.4).
The relative skill of those in the art: The relative skill of those in the art is high, since the use of entecavir as an anti-viral for treating HBV infections has been known for many years relative to the effective filing date of the claimed invention.
The predictability or unpredictability of the art: There is no teaching where entecavir can inhibit or target other DNA polymerases, let alone treat or prevent any diseases related to any DNA polymerase.
The amount of direction or guidance presented/The presence or absence of working examples:
Compounds I-X have been prepared and tested for their ability to degrade DNA polymerase from HBV proteins (see Examples 7, 10, p.28, 32-33).
No other DNA polymerase proteins were tested.
The quantity of experimentation necessary: In order to practice the invention with the full range of all possible treatment methods beyond those known in the art, one skilled in the art would undertake a novel and extensive research program to show that any and all DNA polymerases can be treated/prevented/diagnosed.
In order to determine the efficacy of the claimed therapies in the absence of any existing in vivo data, one skilled in the art would undertake animal testing in order to practice the invention. Animal experiments include, induction of the disease state, administration of the potential pharmaceutical compound and collection and analysis of data, additional burdens associated with compliance with animal welfare regulations, care, feeding and other maintenance of the animals, dissection of dead animals to collect data, and dispose of the dead animals after the research is finished. These trials would need to be run separately and repeatedly for each disorder to be treated, and success in treating each and every disorder would still not be definitive. The experimentation involved would therefore be significant, undue and unpredictable.
Genentech, 108 F.3d at 1366, sates that, “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion.” And “patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable.”
Therefore, in view of the Wands factors, as discussed above, particularly the breadth of the claims, Applicants fail to provide information sufficient to practice the claimed invention for treating, preventing or diagnosing various diseases related to DNA polymerase.
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 1, 4-10, 13 and 14 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.
The recitation “metabolite…thereof” in claim 1, renders the claim and dependent claims 4-10, 13 and 14 herein indefinite. The term is not defined in the Specification. It appears to imply a structure that would be obtained after administering the compound in vivo, in which case, it could include entecavir, the linker, and (S,R,S)-AHPC (the ligand of E3 ubiquitin ligase).
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 14 recites the broad recitation “various diseases related to DNA polymerase”, and the claim also recites “wherein the diseases include but are not limited to viral infectious diseases and secondary diseases” and “preferably the viral infectious disease is infected by hepatitis B virus” which are narrower statements 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.
The recitation “using” in “wherein the method comprises using the bifunctional compound”, and “using the pharmaceutical composition of claim 6” in claim 9, 10, 13 and 14 is not a clear and proper active step, because it’s unclear how the method is actually practiced.
The following structures of claim 4 lack clear antecedent basis from claim 1, at the position indicated:
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;
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;
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.
The genus of the second compound of claim 1 does not include a carboxy group at the indicated positions. None of the linkers recited in claim 1 could be included and arrive at the compounds shown above, in claim 2.
The compound of formula (VI), (VII), (VIII), (IX), and (X) in claim 5 are similarly indefinite.
The recitation “A preparation method of the compound of claim 1, wherein, the compound (I) can be optionally prepared from the following two synthetic routes” in claim 8 lacks antecedent basis, because claim 1 does not recite a compound of formula (I). Similarly, a compound of formula (VI) as recited in claim 8 lacks antecedent basis, because claim 8 does not recite a compound of formula (VI).
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 4-7, 9, 10, 13 and 14 are rejected under 35 U.S.C. 102(a)(1)/(a)(2) as being anticipated by Zahler et al. (US Patent No. 5,206,244, cited in PTO-892).
Zahler et al. disclose a compound having the formula:
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, wherein R1 is
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, R6 and R7 are independently hydrogen, -PO3H2 or -C(=O)R5- (claim 1). Zahler et al. teach an antiviral composition for treating herpes simplex virus 1 and 2, varicella zoster virus, and human cytomegalovirus comprising a pharmaceutically acceptable carrier and an effective amount of the compound of claim 1 (claim 10). Zahler et al. disclose administering an effective amount of the composition of claim 10 for treating herpes simplex virus 1 and 2, varicella zoster virus, and human cytomegalovirus (claim 11).
Thus, Zahler et al. disclose entecavir, a pharmaceutical composition comprising the compound and a pharmaceutically acceptable carrier, and a method of using the compound/composition.
As noted in the rejection under 35 U.S.C. §112(b), the bifunctional compound and “a metabolite…thereof” is broadly and reasonably interpreted to include entecavir.
Thus, the disclosure of Zahler et al. anticipates claims 1, 4-7, 9, 10, 13 and 14 of the present application.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BAHAR A CRAIGO whose telephone number is (571)270-1326. The examiner can normally be reached M-F: Noon-8pm ET.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699