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 .
Election/Restrictions
Applicant’s election without traverse of Group I, (drawn to a conjugate and pharmaceutical compositions comprising thereof), in the reply filed on 11/12/2024 is acknowledged.
Claims 1-10, 13-23, 26, 29 and 30 are pending of which claims 29-30 (Group II) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention there being no allowable generic or linking claim. The restriction requirement is still deemed proper and is made Final.
Pending claims 1-10, 13-23, and 26 have been examined on the merits.
Request for Continued Examination
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 01/13/2026 has been entered.
New Grounds of Rejection due to claim amendment
Claim Rejections - 35 USC § 112
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 1-10, 13-23, and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 5 and 23 encompass a broad genus of conjugates defined by extensive variable as defined by moieties A, Y, E, Z, and L2, wherein each contains multiple optional substitutions comprising a broad range of functional groups. Considering each moiety and its substituents, a person of ordinary skill in the art (POSITA) would then expect thousands of distinct compounds from such combination. The specification, however, provides only limited examples of about 17 compounds (specification page 75-83), which does not represent the full scope of the claimed genus. Thus, the limited variation among the substituents cannot account for the variability across the claimed genus, encompassing at least thousands of compounds. In addition, claims 1 and 5 cover a broad polymer genus, and yet PEG is the only polymer example disclosed in the specification (page 83). It is also worth noting that PEG is not a proper representative of polymeric moiety, because PEG is chemically and functionally distinct from many of the other listed polymer.
Regarding non-enzymatic, physiological condition cleavage between -D+ and -L1-, the specification lacks any working examples demonstrating non-enzymatic cleavage of drug-polymer conjugates, containing the broad A, Y, E, Z, and L2 moieties, under physiological aqueous buffer condition. Given the breadth of the claims, a POSITA would then be required to undue experimentation to determine which combination of the A, Y, E, Z, and L2 would exhibit the claimed non-enzymatic half-life range. Furthermore, considering the unpredictability found in designing a prodrug, changing even one substituent, A, Y, E, Z, and L2 moieties, cannot be considered a foregone conclusion.
Moreover, the limited disclosure in the specification clearly indicates that Applicant was not in possession of the full claimed genus as cited in the instant claims. Consequently, the lack of enablement of the claimed subject matter at the time of filing, suggest that Applicant did not possess supporting data to the claimed invention.
Written Description
Claim 1 recites that -D+ and -L1- is reversible “capable of being cleaved in the absence of enzymes under physiological conditions, which are aqueous buffer at pH 7.4 and 37 °C, and having a half-life ranging from one hour to six months.” The specification (page 79) provides only two specific examples (compound 8a and 8b) in which cleavage was evaluated in vitro at pH 7.4 and 37ºC in aqueous buffer. These examples are limited to a particular small-molecule and don’t represent the full scope of the instant claim, which encompasses broad genus, A, Y, E, Z, and L2 moieties, which clearly lack a polymeric Z moiety. The specification does not report the concentration of the conjugate used in the assay, the quantitative amount of released product, or percent conversion, and therefore the specification does not demonstrate the efficiency or reliability of the non-enzymatic release of the claimed invention. Furthermore, while compounds 5b and 16-17 include a PEG or hydrogel as Z moiety, however, the specification discloses no non-enzymatic cleavage in physiological buffer, and therefore the specification lacks a proper working example of the claimed invention (specification, page 77 and 82). Thus, without quantitative released data, it cannot be concluded that the system predictably achieves the claimed functional limitation.
The specification’s failures to disclose a proper representation of the claimed genus clearly supports the conclusion that the specification lacks adequate written description of the claimed subject matter indicating that Applicant was not in possession of the claimed method at the time of filling of the instant application in view of the disclosure of the application as filed.
Maintained Rejection with changes per claim Amendment
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office
action.
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 1-10, 13-23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Hersel et al. (WO 2005/099768) in view of Gao et al. (Bioorg Med Chem Lett. 2005 Sep 1;15(17):3865-9) and in further of Burke et al. (Mol Cancer Ther. 2016 May;15(5):938-45), Bures F (Top Curr Chem (Cham). 2019 May 6;377(3):14.
Regarding claim 1-10, 13, 15-20, and 22-23, Hersel (page 88, line 15) teaches compound 63, wherein A is phenyl; R2 is absent where t is 0; Y is
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whereY2 is =O; Y3 is -O-; Y1 is -N(R11)- where R11 is methyl; E is propyl; Nu is a tertiary amine; R1 is hydrogen; R1a is hydrogen, but substituted with L2 which is a pentyl and conjugates to Z moiety.
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Hersel does not explicitly teach L1 conjugates to a N+ of a moiety -D+.
However, Gao (page 3866) teaches camptothecin and its derivatives have been
used as chemotherapeutic drugs to treat various cancers like breast cancer, prostate cancer, and lung cancer due to their inhibition activity toward topoisomerase I. Gao (page 3867, Scheme 4) teaches conversion of topotecan tertiary amine to a quaternary amine, to enhance the compound properties. For example, Bures (page 2) teaches quaternary ammonium cations are known to enhance a drug’s solubility and improve its efficacy as bioactive agent.
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Additionally, conjugating the quaternary ammonium compound to a polymer linker, such as L1 and L2, would be expected to enhance the drug’s pharmacokinetic properties, including target specificity.
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For example, Burke (page 938 through 940) teaches quaternary ammonium linkers provide enhanced stability and controlled released of drugs, which are critical for improving the therapeutic index of antibody-drug conjugates (ADCs), as an example. Thus, having quaternary ammonium moiety would provide enhanced solubility and stability, while the polymer linker would offer additional benefits such as increased circulation time and potentially improved targeting. Therefore, it would have been obvious to a person of ordinary skill in the art (POSITA) to combine the teachings of Hersel, Gao and Burke to conjugate a quaternary ammonium linker compound with a polymer linker to enhance drug pharmacokinetic properties.
Regarding formula Ib, Hersel (page 74, line 20; page 95-96) teaches that the phenyl ring is a multi-substituted aromatic hydrocarbon, and a spacer moiety can be one of the substituents. Thus, a person of ordinary skill in the art would have had a reasonable expectation of success in optionally having L2 or L1 or both as substituents on the phenyl ring, which provides flexibility in the arrangements of the linkers to benefit the drug pharmacokinetic.
Regarding physiological pH and absence of enzyme, Hersel (page 16, line 3-9) teaches the following:
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Hersel clearly discloses enzyme-independent, self-cyclizing linker system operating under physiological aqueous buffer of pH 7.4 at 37ºC, with a half-life of 1 hour to 6 months. Although, Hersel does not explicitly disclose a quaternary ammonium drug moiety, Hersel does establish the concept of non-enzymatic, intramolecular triggered release systems in a physiological aqueous buffer. Therefore, a POSITA would recognize Hersel’s teachings as a common general knowledge and regard applying the same non-enzymatic, self-cyclizing linker to a quaternary ammonium system as a routine modification, and not a novel concept. As evidence by Simplicio (page 524) indicating that quaternary ammonium derivatives are expected to cleave at
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physiological pH and release the amine drug. Note, studies at physiological pH are almost conducted in aqueous buffered media, pH 7.4 at 37ºC. Therefore, a POSITA would have been motivated to combine the teachings of Hersel, Gao, Bures, and Burke in view of Simplício to design a quaternary linkage to degrade at physiological pH to release the active drug, because quaternary linkage in a prodrug can be controlled and improved solubility (Simplício, Ana L., et al. “Prodrugs for Amines.” Molecules, vol. 13, no. 3, Mar. 2008, pp. 519–47.)
Moreover, the specification (page 77) discloses compound 5b, comparable to modified
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compound 63 except for the Z moieties (hydrogel vs PEG). However, the specification (page 82-83) also discloses compounds 16a-c and 17, analogous structures differing only at the Z moieties (hydrogel vs PEG). Given that the specification teaches both hydrogel and PEG variants, a POSITA would view these groups as interchangeable, and substitute the PEG with hydrogel from modified compound 63 to arrive at the claimed invention, compound 5b.
Therefore, where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. See MPEP 2112(III).
Where the claimed and prior art products are identical or substantially identical in
structure or composition, or are produced by identical or substantially identical
processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). “When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
…
“Products of identical chemical composition can not have mutually exclusive properties.”
A chemical composition and its properties are inseparable. Therefore, if the prior art
teaches the identical chemical structure, the properties applicant discloses and/or claims
are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658
Regarding claims 3-10, Hersel (page 88, line 15) teaches compound 63, wherein Z moiety is a PEG-based, a water-soluble polymeric moiety. Hersel (page 20, line 29-34 through page 21, line 1-6; page 94, line 1-20) teaches the following:
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Given Hersel teaches various optional polymers that could link with either succinimide or maleimide, thus it would have been obvious for a person of ordinary skill in the art to select polymer that is either a water-soluble or insoluble polymeric to optimize performance across wide range of biomedical and industrial application.
Regarding claim 13-15, Hersel (page 14, line 15-18) teaches
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Regarding claim 20-23, Hersel (page 88, line 15) teaches L2 is a pentyl and forms a stable linker with Z moiety. Hersel does not explicitly disclose the molecular weight of L2. Given the linker is a pentyl, thus, it would have been obvious to a person of ordinary skill in the art to calculate the molecular weight of the linker to be about 71 g/mol.
Regarding claim 26, Hersel (page 1, line 5-7; page 3, line 15-20) teaches polymeric prodrugs which may reduce the risk of side effects and overdosing. Thus, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Hersel, Burke, Bures and Gao which demonstrate the combined effect of prodrug technology and quaternary ammonium cation linker to develop a pharmaceutical composition with enhanced physicochemical and pharmacokinetic properties.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to argument
Applicant argues that the combined teachings of Hersel, Gao and Burke do not teach “capable of being cleaved in the absence of enzymes under physiological conditions, which
are aqueous buffer at pH 7.4 and 37°C, and having a half-life ranging from one hour to six months.” Applicant’s argument is not persuasive because as indicated the 103 rejection above, the combined prior art teaches non-enzymatic cleavage under physiologically relevant aqueous buffer and half-life.
Applicant argues that Hersel does not teach an enzyme-independent self-cyclizing frug-releasing linker system and drug with a quaternary ammonium moiety, and therefore Hersel does not disclose the claimed invention. Applicant further argues that the Examiner does not indicate the proper motivation for combining the references. Applicant argument is not persuasive because Applicant improperly focuses on the deficiencies of the individual refences rather their combined contribution as indicated in the 103 rejection. While Hersel does not teach a quaternary ammonium drug moiety, however, Gao teaches conversion of a tertiary amine to a quaternary amine significantly enhance the compound properties. In addition, Bures (page 2) teaches quaternary ammonium cations are known to enhance a drug’s solubility and improve its efficacy as bioactive agent. Burke (page 938 through 940) teaches quaternary ammonium linkers provide enhanced stability and controlled released of drugs, which are critical for improving the therapeutic index of antibody-drug conjugates (ADCs), as an example. Therefore, it would have been obvious to a POSITA to combine the teachings of Hersel, Gao, Bures and Burke to conjugate a quaternary ammonium linker compound with a polymer linker to enhance drug pharmacokinetic properties. Thus, the combined teachings clearly provide proper motivation of exchanging a carbamate to a quaternary moiety, because such exchange would enhance a drug’s solubility and improve its efficacy as bioactive agent.
A large portion of Applicant’s argument cites deficiencies in a single individual reference, even though obviousness rejection is based on the combined teachings of the prior art, not the limitation of any one reference. 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).
Applicant argues that Gao’s teaching only limited to permanent quaternary ammonium compounds and Goa does not teach a quaternary ammonium moiety to a conjugate structure. Applicant’s argument is not persuasive because Goa discloses campthothecin’s modification, include a quaternary ammonium functionality and explains the associated benefits, including increased polarity. It is well known in the art that adding a polar moiety to a compound can significantly enhance aqueous solubility and alter pharmacokinetic properties, as supported by Burke in the 103 rejection above. Given camptothecin and its derivatives have been used as chemotherapeutic drugs to treat various cancers like breast cancer, prostate cancer, and lung cancer, it would have been obvious to a POSITA to incorporate such a known compound with a quaternary ammonium functional group into a known conjugate system to obtain predictable benefits, as explained in the 103 rejection above.
Applicant argues that Burke is limited to antibody-drug conjugates and does not teach a transient quaternary ammonium compound or a non-enzymatic system. Applicant also argues that Moquist relies on enzyme-dependent cleavage; and that taken together, the combined prior art fails to teach or suggest an enzyme-independent self-cyclizing drug linker conjugated via a quaternary ammonium moiety. Applicant’s argument is not persuasive for the following reasons and those presented in the 103 rejection above: Burke discloses that quaternary ammonium groups can be incorporated into drug-linker system within conjugate systems; and Moquist emphasizes quaternary system based on enzymatic trigger system, and yet combined prior art still establishes the structural framework for self-cleaving linkers, meaning, adding a quaternary ammonium moiety into a complex strucutre. As evidence by Simplicio (page 524) indicating that
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quaternary ammonium derivatives are expected to cleave at physiological pH and release the amine drug, demonstrating that non-enzymatic cleavage of quaternary ammonium species under physiological conditions is known in the art. Therefore, a POSITA would have recognized that the combined teachings of the prior art in view of Simplicio teach (1) quaternary ammonium drug moieties were known and advantageous, (2) quaternary ammonium derivatives were known to undergo degradation at physiological pH without requiring enzymatic intervention.
Conclusion
Therefore, claims 1-10, 13-23, and 26 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622