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Claims 1-10, 13-23, 26, 29, and 30 are pending of which claims 29-30 (Group II) are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention there being no allowable generic or linking claim.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 1-2, 7-9, 14-15, 20-23, and 26, have been examined on the merits.
Withdrawn Rejections
The rejection of claims 1, 5 and 23 under 35 U.S.C. 112(a) is withdrawn in view of the amendments and cancellation.
The rejection of claims 1-10, 13-23, and 26 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 (Mol Cancer Ther. 2016 May;15(5):938-45), Bures F (Top Curr Chem (Cham). 2019 May 6;377(3):14, is withdrawn in view of the amendments and cancellation.
Maintained Rejection, with modification added in response to the 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 1-2, 7-9, 14-15, 20-23, 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.
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
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pH 7.4 and 37ºC in aqueous buffer. However, those examples are limited to a particular small-molecule and don’t represent the claimed hydrogel prodrug structure. In particular, the disclosed examples utilize a relative, A, Y, E, Z, and a simple L2 methyl spacer, and yet lack a polymeric Z or hydrogel moiety. This deficiency is further demonstrated by compounds 5b, 16a, 16b, and 16c (Example 5 and 16), which more closely correspond to the claimed invention because of the spacer associated with the hydrogel moiety (specification page 77 and 82).
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It is important to highlight that the specification provides no cleavage assay or other experimental evidence for compounds of Example 5 and 16, establishing that these structures are capable of cleavage in the absence of an enzyme at physiological pH 7. This creates a significant problem, because the examples that demonstrate cleavage do not represent the claimed structural arrangement, while the example that more closely represents the claimed structural arrangement does not demonstrate the claimed cleavage capability. Thus, the written description clearly leaves a critical gap between the disclosed structures and the claimed functions. Furthermore, 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 clearly demonstrate the efficiency or reliability of the non-enzymatic release of the claimed invention. Finally, the fact that cleavage is demonstrated for structurally different compounds 8a and 8c, while no cleavage evidence is provided for the more representative compounds of Example 5 and 16, clearly supports the conclusion that the specification lacks adequate written description of the claimed subject matter at the time of filling of the instant application.
New Grounds of Rejection due to the Applicant’s Claim Amendments
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 1-2, 7-9, 14-15, 20-23, 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, Okeke et al., Molecules, vol. 24, no. 8, Apr. 2019.
Regarding claims 1-2 and 7-9, 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 (page 88-89) discloses the polymeric is a prodrug system in which different active agents including rhGH, insulin, and GLP-1, are linked to a polymer through a cleavable linker and subsequently released by hydrolysis under aqueous buffer pH 7.4. It is well known in the art that carbamate cleavage is not limited to hydrolysis alone. For example, carbamate groups are known to be removable through multiple condition including hydrogenolysis. As evidenced by TotalSynthesis (page 3-4) disclosing that carbamate can be removed by hydrogenation through complex molecule using Pd/C, H2, to arrive at the complete removal of the carbamate substituent:
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Therefore, a POSTA would understand that a Cbz carbamate derived group can be entirely eliminated or removed, leaving the underlying attachment functionality available to attach another linker such an alkyl halide or with a halide for coupling with an amine containing drug via Menschutkin reactions (see, page 2 and 7). This is supported by Hersel’s teachings (page 22 and 98-99) that an active drug can also be attached to the polymer via other functional group including alkyl halides or haloacetyl. Furthermore, Hersel (page 22) explicitly discloses alkyl halides, as well as carbamate derivatives, as preferred functional groups for attaching the polymer to an active agent. This indicates that carbamate is not required as the only point of attachment between the polymer and the active ingredient. (TotalSynthesis https://total-synthesis.com/cbz-protecting-group/).
Hersel does not explicitly teach L1 conjugates to a N+ of a moiety -D+.
Nonetheless, while Hersel does not explicitly teach use the phrase “quaternary-ammonium containing polymer” but Hersel discloses alkyl halide as functional groups for attachment of the polymer to an amine containing drug. In fact, Okeke (page 2) teaches reaction of a bound alkyl halide with a tertiary amine is a known and predictable quaternization reaction that produces a quaternary-ammonium feature. Thus, a POSA would recognize that an alkyl halide can react with an amine containing active agent, including a tertiary amine, to form a quaternary-ammonium linkage, making such attachment a predictable approach for a prodrug.
Furthermore, Gao (page 3866) teaches camptothecin and its derivatives have been used as chemotherapeutic drugs to treat various cancers including breast cancer and lung cancer. Gao (page 3867, Scheme 4) also teaches conversion of the compound from tertiary amine to a quaternary amine, is a critical step to enhance the compound properties. This is supported by
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Bures’s teachings (page 2) that quaternary ammonium cations are known to enhance a drug’s solubility and improve its efficacy as bioactive agent. Thus, having a quaternary ammonium feature would be expected to enhance the drug’s pharmacokinetic properties, bioavailability, primarily by enhancing aqueous solubility. Furthermore, 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 and Gao in view of Bures, Burke and Okeke to attach a tertiary-amine of compound II to the polymer, as this mechanism is a known and predictable quaternization reaction. Therefore,
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given that camptothecin, including its quaternary complex, has been used as chemotherapeutic drugs and in vivo biomedical imaging, therefore, a POSITA would have been motivated to incorporate camptothecin into a polymer through quaternary-ammonium linker to improve aqueous solubility and provide a controlled-release prodrug with potential prolonged half-life.
Regarding hydrogel, Hersel (page 20-21, 75-76, 88, and 94) discloses that PEG and hyaluronic acid hydrogels can be formed through physical or chemical cross-linking to produce stable polymer network. Hersel (page 20-21) also discloses that hydrogels provide structurally stable, crosslinked, water-swellable matrices with interconnected pores suitable for aqueous environments. Moreover, given the specification (page 75) teaches hydrogel can crosslink with PEG variants to form PEGA-hydrogel, therefore, a POSITA would have been motivated to substitute Suc-PEG5k with a PEG-hydrogel, expecting an improved loading, retention, and controlled released of the active agent, to arrive at the polymeric prodrug illustrated in Example 5 of the specification.
Regarding formula Ib, Hersel (page 74; 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.)
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 cannot 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 claim 14-15, Hersel (page 14, line 15-18) teaches
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Regarding claim 20-23, Hersel (page 88) 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 POSITA to calculate the molecular weight of the linker to be about 71 g/mol, which falls within the claimed range. Although, Hersel does not explicitly use the phrase “spacer,” a POSITA would have understood that the disclosed linker performs the function of a spacer by positioning the polymer or hydrogel component and the active agent apart from one another.
Regarding claim 26, Hersel (page 1 and page 3) 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
Rejections under 35 U.S.C. § 112
Applicant argues that compound 8a and 8b demonstrate possession of the claimed reversible linkage, because the specification identifies L1 as the principal determinant of conjugate half-life. Therefore, there is no need to provide cleavage testing of every individual construct. Applicant’s argument is not persuasive, because compound 8a and 8b do not establish possession of the claimed structural and functional combination as disclosed in the instant application. Although L1 may substantially influence cleavage half-life, it does not establish that polymer-hydrogel portion is functionally irrelevant. On the contrary, Asley (page 2318-2321) discloses the PEG moiety can delay a compound’s renal filtration and thereby increase the plasma half-life of the attached drug. Asley (page 2318-2321) also teaches when β-eliminative linkers are used to tether drug to PEG-hydrogels, the linker controlling drug release and the hydrogel-polymer component controlling polymer degradation can be coordinated to achieve a desirable release profile. Thus, a POSITA would then infer that the polymeric-hydrogel component is not an inert attachment to the L1-D+ linkage and may play functional role in the conjugate’s pharmacokinetic behavior, degradation, and release of the active drug under physiological conditions. Thus, contrary to Applicant’s argument, compounds 8a and 8b are not true representatives of the claimed invention. (Ashley et al. Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2318-23).
Rejections under 35 U.S.C. § 103
Applicant argues that Hersel’s reported hydrolysis and half-life data of polymeric-prodrug containing carbamate, and not a quaternary-ammonium linkage. Thus, Hersel does not demonstrate that a quaternary-ammonium linkage will cleave nonenzymatically at pH 7.4 with the claimed half-life. However, this distinction does not render the claimed system non-obvious. For example, Hersel explicitly mentions alkyl-halide as an attachment point for an amine-containing biologically active agent. Okeke supports this approach by demonstrating that a tertiary amine reacts with an alkyl halide to form a quaternary-ammonium linkage and that the resulting reaction is reversible. Therefore, a POSITA would have recognized that Hersel provides the polymeric-prodrug concept and controlled-release objective, while Okeke provides the known chemistry for converting the disclosed tertiary amine/alkyl-halide combination into a reversible quaternary-ammonium attachment. Therefore, the fact that Hersel’s experimental half-life data were obtained with carbamate linkages does not refute the obviousness determination. Furthermore, Hersel’047 teaches that nonenzymatic physiological cleavage half-life is a linker design parameter, not a property unique to Hersel’s carbamate examples. For instance, Hersel’047 (page 9) defines reversible prodrug linkers as non-enzymatically hydrolytically cleavable at pH 7.4 and 37ºC, with example half-lives of about 1 hour to 3 months, while stable linkers have half-life of at least 6 months. This suggests that half-life is a characteristic of the polymer prodrug system, while still permiting the use of different linkers for attaching the active agent, comparable to Hersel’s teachings. Therefore, a POSITA would have expected the polymer platform to provide controlled and predictable release even when the particular attachment, including carbamate, alkyl halide or quaternary-ammonium linkage, is varied, with the release kinetics is being controlled though linker design. (Hersel et al., WO2013024047A1 “Hersel’047”)
Furthermore, Applicant’s argument of an unexpected improvement from combining the quaternary-ammonium linkage with a polymeric carrier, is not persuasive. As related above in the § 103 rejection, Hersel discloses alkyl halide as a functional group for attachment of the polymer to an amine containing drug. Moreover, Okeke teaches reaction of a bound alkyl halide with a tertiary amine is a known and predictable quaternization reaction that produces a quaternary-ammonium feature. Furthermore, Burke teaches quaternary ammonium linkers provide enhanced stability and controlled released of drugs, improve drug solubility and bioavailability, thereby enhancing delivery and efficacy. Therefore, omitting the carbamate feature in favor of a quaternary-ammonium linkage, would have been a predictable modification based on known pharmaceuticals benefits. Therefore, a POSITA would have reasonably recognized quaternary-ammonium linkage, as an alternative to carbamate, making such feature or exchange predictable.
Moreover, 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 also argues that a POSITA would not have found it obvious to replace Suc-PEG5K with hydrogel moiety, and, thus would require undue experimentation. Applicant’s argument is not persuasive, because Hersel explicitly identifies hydrogels as suitable polymer carriers, and provides advantageous swelling and aqueous properties. Hersel also provides general synthesis routes for incorporating the polymer carrier into the prodrug. Thus, Hersel provides both the motivation and a practical approach for substituting Suc-PEG5k with a hydrogel, such that the modification would have been recognized as routine experimentation by a POSITA, rather than undue experimentation.
Applicant further argues that the prior art disclosing quaternary-ammonium containing compounds does not explicitly disclose the specific compound structure or the claimed release linker. Applicant’s argument is not persuasive, because those references served the purpose to establish the beneficial properties of quaternary-ammonium functional group were already known in the art, and not to disclose Hersel’s polymeric release-linker system. Hersel already teaches the polymeric prodrug framework, release linkers, and alternative attachment components. Thus, a POSITA would have recognized the benefits of quaternary-ammonium properties and would have been motivated to incorporate them into d Hersel’s polymeric prodrug system, without first requiring the quaternary-ammonium references to disclose all the claimed polymer or linker.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 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
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