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 .
Formal Matters
Receipt of Applicant’s response, dated 11/06/2025, is acknowledged.
Claims 1-19, 21-24, and 28 are pending.
Claims 20 and 25-27 are canceled.
Claims 1-5, 7, 9, 13, and 18 are amended.
Claim 28 remains withdrawn from consideration as being drawn to a nonelected invention.
Claims 6, 8, 10-11, and 21-24 remain withdrawn from consideration as being drawn to nonelected species.
Claims 1-5, 7, 9, and 12-19 are under consideration in the instant Office action to the extent of the elected species, i.e., the ionizable drug or ionizable drug analogue is lapatinib, the stabilizing agent is fulvestrant, and the targeting compound is transferrin.
OBJECTIONS/REJECTIONS WITHDRAWN
Claim Objections
The objections to claims 2-5, 9, 13, and 18 set forth in the Office action dated 05/06/2025 are hereby withdrawn in light of Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112
The indefiniteness rejection of claims 7 and 9 set forth in the Office action dated 05/06/2025 is hereby withdrawn in light of Applicant’s amendments to the claims.
REJECTIONS MAINTAINED
Claim Rejections - 35 USC § 103
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.
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 1-5, 7, 9, and 12-19 are rejected under 35 U.S.C. 103 as being unpatentable over Sengupta et al (US 9,789,193 B2, published 10/17/2017, cited in Notice of References Cited dated 05/06/2025) in view of Emde et al (Tumor Biology and Human Genetics, 2007 ASCO Annual Meeting, published 06/20/2007, cited in Notice of References Cited dated 05/06/2025) and Daniels et al (Biochim. Biophys. Acta., 2011, 1820, 291-317, published 08/05/2011, cited in Notice of References Cited dated 05/06/2025).
Sengupta et al teach compositions comprising a conjugate that increase the level of a chemotherapeutic agent delivered to a tumor while reducing the accumulation of the chemotherapeutic agent in other tissues, wherein the compositions have improved release kinetics over typical nanoformulations of chemotherapeutic agents (e.g., Col. 1 Lines 49-57).
The conjugate comprises a chemotherapeutic agent conjugated to a lipid (e.g., cholesterol) (e.g., Col. 1 Lines 58-59, 11, Col. 11 Lines 52-54).
The chemotherapeutic agent may be an anti-estrogen including fulvestrant (e.g., Col. 13 Lines 56-57, 151). The composition can further comprise an anti-cancer agent including lapatinib (e.g., Col. 5 Lines 57-59, Col. 6 Line 8).
The chemotherapeutic agent and the lipid (e.g., cholesterol) can be linked together by a cleavable linker which is used to release the chemotherapeutic agent after transport to the desired target cell (e.g., Col. 19 Lines 32-39). The cleavable linker comprises at least one cleavable linking group which is sufficiently stable outside of the target cell but upon entry into a target cell is cleaved to release the two parts the linker is holding together (e.g., Col. 20 Lines 32-36). The cleavable linker may be cleaved by endosomes or agents that can create an acidic environment, e.g., those that result in a pH of five or lower (e.g., Col. 20 Lines 45-56).
The composition can be a microparticle or nanoparticle that is part of a network or an aggregate and can be in the form of an emulsion (e.g., Col. 27 Lines 13-25, Col. 29 Lines 51-54).
The composition can further comprise a targeting agent, including proteins, wherein the targeting agent is chosen specific to a cell type or tissue (e.g., Col. 5 Lines 43-46, Col. 25 Lines 23-26). The targeting agent can be linked to a component (e.g., lipid) of the composition (e.g., Col. 25 Lines 46-48).
Sengupta et al do not teach a rationale for the specific combination of fulvestrant and lapatinib nor do they teach transferrin as a suitable targeting agent.
These deficiencies are made up for in the teachings of Emde et al and Daniels et al.
Emde et al teach the combination of fulvestrant and lapatinib in EGFR and HER2 overexpressing and non-overexpressing breast cancer cell lines and found a synergistic action of lapatinib and fulvestrant (e.g., Background, Conclusion).
Daniels et al teach that the transferrin receptor is an attractive molecule for the targeted therapy of cancer tumors since it is upregulated on the surface of many cancer types (e.g., Abstract). Daniels et al teach transferrin-chemotherapeutic drug conjugates, wherein transferrin has been conjugated to a chemotherapeutic drug in order to avoid the adverse side effects of the drug in a free condition, while helping direct and localize the drug to its target (e.g., Par. 1 of 3.1.1.2).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to use fulvestrant as the chemotherapeutic agent, lapatinib as the anti-cancer agent, and transferrin as the targeting agent in the composition of Sengupta et al. One of ordinary skill in the art would have been motivated to do so in order to direct the composition of Sengupta et al to target breast cancer tumor cells. There would have been a reasonable expectation of success because 1) the composition of Sengupta et al is compatible with fulvestrant as a chemotherapeutic agent, lapatinib as an anti-cancer agent, and targeting agents including proteins, for which transferrin is protein, 2) Emde et al teach the compatibility and synergy of fulvestrant and lapatinib, and 3) Daniels et al teach the compatibility of conjugates of transferrin and chemotherapeutic drugs.
The modified composition of Sengupta et al in view of Emde et al and Daniels et al comprising fulvestrant as the chemotherapeutic agent, lapatinib as the anti-cancer agent, and transferrin as the targeting agent, and in the form of emulsified nano-sized aggregated particles renders obvious the composition of instant claims 1-5, 7, 9, and 12-19.
The modified composition of Sengupta et al being a nanoparticle that is part of an aggregate and in the form of an emulsion renders obvious the composition comprising a colloidal aggregate of the instant claims because an emulsion is a type of colloid.
The chemotherapeutic agent and the lipid of the modified composition of Sengupta et al being configured to be cleaved by endosomes or agents that can create an acidic environment, e.g., those that result in a pH of five or lower renders obvious the composition being acid-responsive and disrupting, dissolving, or disassembling when in an acid environment having a pH of less than 7.4 (as required by instant claim 1) or less than about 6.5 (as required by instant claim 2). A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art (In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003)).
The functional properties of lapatinib of instant claims 3-4 are necessarily present in the modified composition of Sengupta et al because the modified composition of Sengupta et al comprises lapatinib. Similarly, the functional properties of fulvestrant of instant claims 5 and 9 are necessarily present in the modified composition of Sengupta et al because the modified composition of Sengupta et al comprises fulvestrant. 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 (Fed. Cir. 1990).
The modified composition of Sengupta et al being configured to be cleaved by endosomes in a target cell releasing its components renders obvious the composition disrupting, dissolving or disassembling in a stomach acid, or a lysosome or an endosome of a cell releasing the one or more drugs as is required by instant claims 13 and 14.
The modified composition of Sengupta et al comprising a targeting agent chosen to be specific to a cell type or tissue as transferrin, which binds to the transferrin receptor in cancer tumor cells (supra), renders obvious the composition of instant claims 15-17. The functional properties of transferrin and fulvestrant of instant claim 18 is necessarily present in the modified composition of Sengupta et al because the modified composition of Sengupta et al comprises transferrin and fulvestrant. 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 (Fed. Cir. 1990).
Response to Applicant’s Arguments
Applicant’s arguments filed on 11/06/2025 have been considered.
Applicant argues that the conjugate of Sengupta et al in a microparticle or nanoparticle that is in an emulsion differs both structurally and functionally from the colloidal aggregate of the present application and that the skilled person having regard to Sengupta et al could not have been led to the presently claimed colloidal aggregate and would have had no motivation to make or use such colloidal aggregates. Applicant argues that the colloidal aggregate of the present application is formed from one or more drugs and a stabilizing agent, wherein the colloidal aggregate disrupts, dissolves, or disassembles when the acid-responsive composition is in an acidic environment having a pH of less than 7.4, which was designed to facilitate dissolution of stable drug colloids only when in an acidic environment, which is distinctly different technology than the compositions of Sengupta et al which utilize a conjugate comprising a drug covalently bound to a lipid (e.g., cholesterol) via an acid-labile cleavable linker. Applicant argues that the composition of Sengupta et al does not contain a colloidal aggregate of one or more drugs and a stabilizing agent, and rather it may be a nanoparticle or emulsion that contains a drug-lipid conjugate with a cleavable linker between the drug and lipid.
The above arguments have been fully considered by the Examiner but are not found persuasive because the modified composition of Sengupta et al in view of Emde et al and Daniels et al meets the limitations of the composition as instantly claimed. Specifically, as can be seen in the maintained grounds of rejection under 35 USC 103 above, the modified composition of Sengupta et al being a nanoparticle that is part of an aggregate and in the form of an emulsion (an emulsion is a type of colloid) renders obvious the composition comprising a colloidal aggregate and the chemotherapeutic agent and the lipid of the modified composition of Sengupta et al being configured to be cleaved by endosomes or agents that can create an acidic environment, e.g., those that result in a pH of five or lower, renders obvious the composition being acid-responsive and disrupting, dissolving, or disassembling when in an acid environment having a pH of less than 7.4. The argument that “the skilled person having regard to Sengupta et al could not have been led to the presently claimed colloidal aggregate and would have had no motivation to make or use such colloidal aggregates” has been fully considered by the Examiner but is not found persuasive because the rejection under 35 USC 103 of claims 1-5, 7, 9, and 12-19 is based on the combined teachings of Sengupta et al, Emde et al, and Daniels et al and not solely on the teaching of Sengupta et al. Applicant is remined that 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). As can be seen in the maintained grounds of rejection under 35 USC 103 above, based on the teachings of Sengupta et al, Emde et al, and Daniels et al, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to use fulvestrant as the chemotherapeutic agent, lapatinib as the anti-cancer agent, and transferrin as the targeting agent in the composition of Sengupta et al in order to direct the composition of Sengupta et al to target breast cancer tumor cells and there would have been a reasonable expectation of success because the composition of Sengupta et al is compatible with fulvestrant as a chemotherapeutic agent, lapatinib as an anti-cancer agent, and targeting agents including proteins, for which transferrin is protein, Emde et al teach the compatibility and synergy of fulvestrant and lapatinib, and Daniels et al teach the compatibility of conjugates of transferrin and chemotherapeutic drugs. The argument that the colloidal aggregate of the present application “was designed to facilitate dissolution of stable drug colloids only when in an acidic environment” has been fully considered by the Examiner but is not found persuasive because the prior art is not required to teach the same motivation for composition design as Applicant, i.e., the prior art needs to provide a motivation and not the same motivation as Applicant or necessarily recognize the same problem/solution as Applicant. "In determining whether the subject matter of a patent claim is obvious, neither the particular motivation nor the avowed purpose of the patentee controls." KSR Int'l Co. v. Teleflex lnc., 550 U.S. 398,419 (2007). Instead, "any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed." Id. at 420. In response to Applicant’s argument that the colloidal aggregate of the present application is different technology than the modified composition of Sengupta et al in view of Emde et al and Daniels et al, the Examiner encourages Applicant to amend the claims in order to distinguish this technology from that taught by Sengupta et al in view of Emde et al and Daniels et al.
Applicant argues that neither Emde et al nor Daniels et al teach or suggest any formation of a colloidal aggregate of one or more drugs and a stabilizing agent as required by the present claims. Applicant argues that it is not accurate that the limitations of instant claims 3-5 and 9 are necessarily present because even in the modified composition of Sengupta et al, the properties of lapatinib and fulvestrant would not be the same as in the presently claimed composition because, in the modified composition of Sengupta et al, at least one of lapatinib and fulvestrant would be covalently linked to a lipid via an acid-labile, cleavable linker, and consequently, the chemical and functional properties of lapatinib and/or fulvestrant in the modified composition of Sengupta et al would be chemically and functionally changed in comparison to their properties in the presently claimed composition. Applicant argues that accordingly, the combination of Sengupta et al with one or both of Emde et al and Daniels et al does not teach the chemical structure of properties of the composition as presently claimed.
Firstly, the Examiner makes note that the rejection under 35 USC 103 of claims 1-5, 7, 9, and 12-19 is based on the combined teachings of Sengupta et al, Emde et al, and Daniels et al and not “the combination of Sengupta et al with one or both of Emde et al and Daniels et al” as argued by Applicant. The argument that “neither Emde et al nor Daniels et al teach or suggest any formation of a colloidal aggregate of one or more drugs and a stabilizing agent as required by the present claims” has been fully considered by the Examiner but is not found persuasive because the rejection under 35 USC 103 of claims 1-5, 7, 9, and 12-19 is based on the combined teachings of Sengupta et al, Emde et al, and Daniels et al and not solely on the combined teachings of Emde et al and Daniels et al. Applicant is remined that 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). As can be seen in the maintained grounds of rejection under 35 USC 103 above, based on the teachings of Sengupta et al, Emde et al, and Daniels et al, it would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to use fulvestrant as the chemotherapeutic agent and lapatinib as the anti-cancer agent in the composition of Sengupta et al (based on the teachings of Emde et al) and to use transferrin as the targeting agent in the composition of Sengupta et al (based on the teachings of Daniels et al) in order to direct the composition of Sengupta et al to target breast cancer tumor cells and there would have been a reasonable expectation of success because the composition of Sengupta et al is compatible with fulvestrant as a chemotherapeutic agent, lapatinib as an anti-cancer agent, and targeting agents including proteins, for which transferrin is protein, Emde et al teach the compatibility and synergy of fulvestrant and lapatinib, and Daniels et al teach the compatibility of conjugates of transferrin and chemotherapeutic drugs. The argument that the limitations of instant claims 3-5 and 9 would not necessarily be present in the modified composition of Sengupta et al has been fully considered by the Examiner but is not found persuasive because the Examiner does not consider the remark made by Applicant that “in the modified composition of Sengupta et al…at least one of lapatinib and fulvestrant would be covalently linked to a lipid via an acid-labile, cleavable linker…consequently, the chemical and functional properties of lapatinib and/or fulvestrant in the modified composition of Sengupta et al would be chemically and functionally changed in comparison to their properties in the presently claimed composition” sufficient evidence that the limitations of instant claims 3-5 and 9 would not necessarily be present. 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 (Fed. Cir. 1990). Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention (In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979)).
Conclusion
No claims are allowable.
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.
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/K.E.O./Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619