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 claims priority to the application, 63/161,719 and PCT/US2022/0071137, with the effective filing dates of 16 Mar 2021 and 14 Mar 2022, respectively.
Claim Status
This Office Action is in response to Applicant’s Amendment filed, 29 June 2026, wherein Applicant amended claims 1 and 4 and canceled claim 3. Claims 2, 14-25, 27, and 29-34 were previously canceled.
Applicant previously elected Group I (claims 1-25 and 34) and Compound 11 (
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) as the species. Claims 7-10, 26, and 28 were withdrawn as they are directed to a nonelected group or species.
Claims 1, 4-6, and 11-13 are under consideration in the instant office action.
Information Disclosure Statement
The Information Disclosure Statement filed on 29 June 2026 and the references cited
therein have been considered, unless indicated otherwise.
Rejections Maintained
Claim Rejections – 35 U.S.C. § 103
1. (Maintained) Claims 1, 3-4, and 11 were rejected as being unpatentable under 35 U.S.C. 103 over Zhang (U.S. Patent Publication No. 2020/0239513, published 30 Jul 2020, see IDS 6 Feb 2026; of record, see PTO-892 mailed 30 Mar 2026) in view of Rautio (Nat Rev Drug Discovery, 2008, 7, 255-270; of record, see PTO-892 mailed 30 Mar 2026), Jung (Molecules, 2018, 23(731), 1-12; of record, see PTO-892 mailed 30 Mar 2026), and Mehellou (J. Med. Chem., 2018, 61, 2211-2226; of record, see PTO-892 mailed 30 Mar 2026) as evidenced by Organic Portal 1 (“Esterifications,” Organic Portal, 2026, <https://www.organic- chemistry.org/synthesis/C1O/esters/esterifications.shtm>, accessed 20 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026) and Organic Portal 2 (“P-O Bond Formation,” Organic Portal, 2026, <https://www.organic- chemistry.org/synthesis/P1O/index.shtm>, accessed 20 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026). Claim 3 was canceled.
Applicant’s arguments, see pages 9-14, have been fully considered but they are not persuasive.
Applicant argues that Zhang does not suggest that the naphthyl group should be modified or replaced. Applicant asserts that Rautio notes that a challenge with ester prodrugs is the accurate prediction of pharmacokinetic disposition in humans. Applicant asserts that Jung does not disclose or suggest modifying ETV with anything other than a fatty acid nor does it suggest esterification at the compound’s other hydroxyl site. Applicant asserts that Mehellou teaches away from phenyl esters, because Mehellou reports that the naphthyl esters yield more active ProTides than their phenyl ester counterparts due to higher lipophilicity. Applicant then asserts that the Examiner used impermissible hindsight as there was no motivation to make the phenyl ester.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, one of ordinary skill in the art would have been motivated to make such a selection, with a reasonable expectation of success, because:
-Zhang teaches prodrugs of entecavir for treating hepatitis B virus (HBV),
-Zhang specifically teaches substitution at R1 and R2 (pages 5 and 6),
-Zhang teaches substituting R2 as the naphthyl ester:
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(page 5),
-Zhang teaches that modifications to entecavir are to develop a prodrug that will be
released slowly, sustainably, and steadily in order to achieve a long-acting effect (abstract),
-Zhang teaches that 130 million people in China are infected with chronic HBV ([0004]),
-Zhang teaches that about 500,000 people die from hepatopathy every year, leading to a large economic impact ([0004]),
-Zhang teaches that HBV is a chronic disease, which requires long-lasting medicine to control the virus level in the body ([0005]),
-Zhang teaches there is no long-acting preparation of entecavir ([0005]),
-Zhang suggests that R1 and R2 can both be an ester ([0009]-[0013]),
-Rautio teaches ester prodrugs and derivatives thereof,
-Rautio teaches that esters are the most common prodrugs used to enhance lipophilicity and thus passive membrane permeability,
- Rautio teaches that carboxyl and phosphate esters are both straightforward to synthesize as evidenced by Organic Portal 1 and Organic Portal 2,
-Rautio teaches di-substituted ester prodrugs: dipivefrin and bambuterol and that the di- substituted ester prodrug, dipivefrin, penetrates the human cornea 17-times more rapidly than the parent drug (adrenaline) due to its lipophilicity,
-Rautio teaches a di-substituted prodrug ester derivative (bambuterol, a carbamate) with sustained drug action due to protection of the hydroxyls to avoid first-pass intestinal and hepatic metabolism,
-Rautio teaches that because of the prolonged action, the prodrug is administered once- daily as opposed to the parent drug, which is administered three times a day,
-Rautio teaches that there is a comprehensive review on ester prodrugs that enhance oral absorption of predominantly poorly permeable and polar parent drugs that was recently published in 2008 (page 256, column 2, paragraph 3),
-Jung teaches mono-substituted prodrugs of entecavir, which possesses low permeability in the GI tract,
-Jung teaches that there is a negative food effect in entecavir oral therapy on intestinal absorption, that the patient experiences a decrease in the extent of drug absorption (18-20%), and that alternative entecavir dosage forms are needed to minimize negative food effects on intestinal absorption,
-Mehellou teaches benzyl ester ligands on phosphate prodrugs for HIV and hepatitis B virus (page 2211, column 1, paragraph 1),
-Mehellou teaches that nucleoside drugs often demonstrate poor oral bioavailability due to low intestinal permeability (page 2211, column 2, paragraph 1),
-Mehellou teaches that benzyl esters are more slowly hydrolyzed than naphthyl counterparts (page 2217, column 1, paragraph 2),
-Mehellou teaches that benzyl esters are used as masks in prodrugs for targeting HIV in similar scaffolds and that those prodrugs are now in clinical trials,
-Mehellou teaches the compounds,
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and
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, with benzyl and naphthyl ester ligand, which are now in clinical trials,
-Mehellou teaches that the 2-naphthyl ester analog was more potent than the benzyl ester, but also that the 1-naphthyl was less potent than the benzyl ester, which is different than the phenyl ester (Figure 7, page 2217),
-Mehellou teaches that the naphthyl-containing ProTides exhibited better biological activity than their phenyl counterparts but does not comment on or compare the naphthyl esters to the benzyl esters and differentiates between phenyl and benzyl in Figure 7 (page 2217, column 1, paragraph 3),
-however, Mehellou teaches that the phenyl esters are still utilized and explored in conjunction with the naphthyl esters, because the biological activity is often correlated with lipophilicity (page 2217, column 1, paragraph 3),
-Mehellou teaches that that Compound 1 (NUC-1031, containing a benzyl ester and phenyl ester) is able to effectively overcome gemcitabine resistance and has an increased safety profile due to less production of the toxic metabolite, 2’,2’-difluorodexoyuridine (Figure 10, page 2218; page 2218, column 1, paragraphs 5-6; page 2218, column 2, paragraph 1),
-Mehellou teaches that Compound 1 (NUC-1031) had better pharmacokinetics than its parent drug and was effective in a variety of different cancers (page 2219, column 1, paragraphs 1-2),
-Mehellou teaches that Compound 2 (NUC-3373, containing a benzyl ester and naphthyl ester) was more cytotoxic in tumor cells than its comparator drug, 5-fluoro-2’-deoxyuridine (page 2219, column 1, paragraphs 3-4), and
-Accordingly, Mehellou does not teach away from benzyl or phenyl esters and instead teaches their successful incorporation in clinical trials (Figure 10, page 2218; page 2218, column 1, paragraphs 5-6; page 2218, column 2, paragraph 1; page 2219, column 1, paragraph 2; page 2219, column 1, paragraphs 3-4).
As such, a person or ordinary skill would have been motivated to combine the selected teachings to predictably arrive at Compound 11
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.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Thus, the rejection of claims 1, 4, and 11 as being unpatentable over Zhang in view of Rautio, Jung, and Mehellou as evidenced by Organic Portal 1 and Organic Portal 2 is maintained.
2. (Maintained) Claims 5-6 were rejected as being unpatentable under 35 U.S.C. 103 over Zhang (U.S. Patent Publication No. 2020/0239513, published 30 Jul 2020, see IDS 6 Feb 2026; of record, see PTO-892 mailed 30 Mar 2026) in view of Rautio (Nat Rev Drug Discovery, 2008, 7, 255-270; of record, see PTO-892 mailed 30 Mar 2026), Jung (Molecules, 2018, 23(731), 1-12; of record, see PTO-892 mailed 30 Mar 2026), and Mehellou (J. Med. Chem., 2018, 61, 2211-2226; of record, see PTO-892 mailed 30 Mar 2026) as evidenced by Organic Portal 1 (“Esterifications,” Organic Portal, 2026, <https://www.organic- chemistry.org/synthesis/C1O/esters/esterifications.shtm>, accessed 20 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026) and Organic Portal 2 (“P-O Bond Formation,” Organic Portal, 2026, <https://www.organic- chemistry.org/synthesis/P1O/index.shtm>, accessed 20 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026) as applied to claims 1, 4, and 11 above, and further in view of Morissette (Adv. Drug Delivery Rev., 2004, 56, 275-300; of record, see PTO-892 mailed 30 Mar 2026).
Applicant’s arguments, see pages 14-15, have been fully considered but they are not persuasive.
Applicant asserts that none of Zhang, Rautio, Jung, or Mehellou disclose or suggest Compound 11, much less a crystalline compound. Additionally, Applicant argues that Morissette provides no guidance regarding possible crystalline forms of Compound 11 and instead provides a discussion of the use of high-throughput screening to discover polymorphs. Applicant then argues that the Federal Circuit has made it clear that polymorph patent claims are not obvious when the cited reference simply provides “a general approach” to polymorph screening without providing “detailed enabling methodology.” Grunenthal GmbH v. Alkem Labs. Ltd., 919 F.3d 1333, 1345 (Fed. Cir. 2019).
In response to Applicant’s assertion that none of Zhang, Rautio, Jung, or Mehellou disclose or suggest Compound 11, Applicant relies upon the argument over claims 1, 4, and 11 to overcome the rejection of claims 5-6. However, Applicant’s arguments over claims 1, 4, and 11 were not persuasive.
In response to Applicant’s argument that Morissette provides no guidance regarding possible crystalline forms and the Federal Circuit has made it clear that polymorph patent claims are not obvious when the cited reference simply provides “a general approach” to polymorph screening without providing “detailed enabling methodology, the Examiner notes that Morissette teaches high throughput crystallization systems that have been developed to more rapidly and comprehensively explore the multiparameter space that contributes to solid form diversity (page 278, column 2, paragraph 2). In other words, Morissette teaches detailed enabling methodology that enables a person of skill in the art to rapidly generate and screen through many polymorphs and tens of thousands of crystallization setups in order to generate all the possible polymorphs of a particular compound (page 289, column 2, paragraph 3; page 290, column 1, paragraph 1; page 288, column 1, paragraph 1). Additionally, the Federal Circuit states that the prior art cited therein only presents a flow chart that outlines a number of variables that may be adjusted during the recrystallization process to determine whether polymorphism occurs in a compound and only notes that the parameters should be varied (page 13, paragraph 2; page 14, paragraph 2; page 15, paragraph 1). Further, the Federal Circuit in Grunenthal GmbH v. Alkem Labs Ltd. does not specify a high throughput screening methodology and thus does not assess the technical ability to screen tens of thousands of solvents in a high throughput screen as taught by Morissette, wherein Morissette provides a method to evaluate all possible solvents to generate all possible polymorphs to save time and reduce costs (page 28, column 2, paragraph 2; page 288, column 1, paragraph 1). Thus, it would be obvious to try as there were a finite number of identified, predictable potential solutions identified by Morissette.
Thus, the rejection of claims 5-6 as being unpatentable over Zhang in view of Rautio, Jung, and Mehellou as evidenced by Organic Portal 1 and Organic Portal 2 and further in view of Morissette is maintained.
3. (Maintained) Claim 12 was rejected as being unpatentable under 35 U.S.C. 103 over Zhang (U.S. Patent Publication No. 2020/0239513, published 30 Jul 2020, see IDS 6 Feb 2026; of record, see PTO-892 mailed 30 Mar 2026) in view of Rautio (Nat Rev Drug Discovery, 2008, 7, 255-270; of record, see PTO-892 mailed 30 Mar 2026), Jung (Molecules, 2018, 23(731), 1-12; of record, see PTO-892 mailed 30 Mar 2026), and Mehellou (J. Med. Chem., 2018, 61, 2211-2226; of record, see PTO-892 mailed 30 Mar 2026) as evidenced by Organic Portal 1 (“Esterifications,” Organic Portal, 2026, <https://www.organic- chemistry.org/synthesis/C1O/esters/esterifications.shtm>, accessed 20 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026) and Organic Portal 2 (“P-O Bond Formation,” Organic Portal, 2026, <https://www.organic- chemistry.org/synthesis/P1O/index.shtm>, accessed 20 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026) as applied to claims 1, 4, and 11 above, and further in view of Ahmed (WO 2017/119936, published 13 July 2017; of record, see PTO-892 mailed 30 Mar 2026).
Applicant’s arguments, see page 15, have been fully considered but they are not persuasive.
Applicant asserts that none of Zhang, Rautio, Jung, or Mehellou disclose or suggest Compound 11, and thus Ahmed does not render the claimed pharmaceutical composition obvious. Applicant argues that Ahmed is directed to injectable formulations for poorly water-soluble active pharmaceutical ingredients.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s assertion that none of Zhang, Rautio, Jung, or Mehellou disclose or suggest Compound 11, Applicant relies upon the argument over claims 1, 4, and 11 to overcome the rejection of claim 12. However, Applicant’s arguments over claims 1, 4, and 11 were not persuasive.
Thus, the rejection of claim 12 as being unpatentable over Zhang in view of Rautio, Jung, and Mehellou as evidenced by Organic Portal 1 and Organic Portal 2 and further in view of Ahmed is maintained.
4. (Maintained) Claim 13 was rejected as being unpatentable under 35 U.S.C. 103 over Zhang (U.S. Patent Publication No. 2020/0239513, published 30 Jul 2020, see IDS 6 Feb 2026; of record, see PTO-892 mailed 30 Mar 2026) in view of Rautio (Nat Rev Drug Discovery, 2008, 7, 255-270; of record, see PTO-892 mailed 30 Mar 2026), Jung (Molecules, 2018, 23(731), 1-12; of record, see PTO-892 mailed 30 Mar 2026), and Mehellou (J. Med. Chem., 2018, 61, 2211-2226; of record, see PTO-892 mailed 30 Mar 2026) as evidenced by Organic Portal 1 (“Esterifications,” Organic Portal, 2026, <https://www.organic- chemistry.org/synthesis/C1O/esters/esterifications.shtm>, accessed 20 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026) and Organic Portal 2 (“P-O Bond Formation,” Organic Portal, 2026, <https://www.organic- chemistry.org/synthesis/P1O/index.shtm>, accessed 20 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026) as applied to claims 1, 4, and 11 above, and further in view of Patel (Int. J. Mol. Sci., 2020, 21(8224), 1-21; of record, see PTO-892 mailed 30 Mar 2026) as evidenced by Wikipedia 1 (“Carboxymethyl cellulose,” Wikipedia, <en.wikipedia.org/wiki/Carboxymethyl_cellulose>, 2026, accessed 11 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026), Wikipedia 2 (“Hypromellose,” Wikipedia, 2026 <en.wikipedia.org/wiki/Hypromellose>, accessed 11 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026), and Wikipedia 3 (“Hydroxypropyl cellulose,” Wikipedia, 2026, <en.wikipedia.org/wiki/Hydroxypropyl_cellulose>, accessed 11 Mar 2026; of record, see PTO-892 mailed 30 Mar 2026).
Applicant’s arguments, see page 15, have been fully considered but they are not persuasive.
Applicant asserts that none of Zhang, Rautio, Jung, or Mehellou disclose or suggest Compound 11, and thus Patel does not render the claimed pharmaceutical composition obvious. Applicant argues that Patel is directed to commonly used excipients on the inhibition of CYP450 enzymes, which plays a role in first-pass metabolism.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s assertion that none of Zhang, Rautio, Jung, or Mehellou disclose or suggest Compound 11, Applicant relies upon the argument over claims 1, 4, and 11 to overcome the rejection of claim 13. However, Applicant’s arguments over claims 1, 4, and 11 were not persuasive.
Thus, the rejection of claim 13 as being unpatentable over Zhang in view of Rautio, Jung, and Mehellou as evidenced by Organic Portal 1 and Organic Portal 2 and further in view of Patel as evidenced by Wikipedia 1, Wikipedia 2, and Wikipedia 3 is maintained.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Madeline M Dekarske whose telephone number is (571)272-1789. The examiner can normally be reached Monday - Thursday 10am - 4pm.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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