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 .
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 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.
Priority
The instant application, filed 04/14/2023, is a 371 filing of PCT/US2021/055434, filed 10/18/2021, and claims domestic benefit to US provisional application 63/092,611, filed 10/16/2020.
Status of Application, Amendments, and/or Claims
Applicant’s response of 03/09/2026 is acknowledged. Claims 5, 8, 15, 19, 22, and 34 are amended; claims 12, 14, 16, 18, 20, 23, 25-28, 32-33, and 35-40 are cancelled; and claims 41-44 are new. Claims 1-11, 13, 15, 17, 19, 21-22, 24, 29-31, 34, and 41-44 are currently pending and are examined on the merits herein.
Withdrawn Objections and Rejections
In the office action of 12/08/2025,
The sequence disclosure was objected to. Applicant’s amendment to the sequence listing and the specification to provide a SEQ ID NO for the pentapeptide has overcome the objection and the objection is withdrawn.
The specification was objected to. The compound on the last row of Table A is fully legible and the objection is withdrawn.
Claim 8 was objected to. Correction of the spelling of “alkynylheteroaryl” has overcome the objection and the objection is withdrawn.
Claims 22 and 34 were objected to. Applicant’s amendment to use all commas to separate the Markush group species has overcome the objections and the objections are withdrawn.
Claims 5 and 6 were rejected under 35 USC 112(b). Applicant’s amendment to remove the optional limitation from claim 5 has overcome the rejections and the rejections are withdrawn.
Claims 8 and 9 were rejected under 35 USC 112(b). Applicant’s amendment to claim 8 to clarify the linkers claimed has overcome the rejections and the rejections are withdrawn.
Claim 15 was rejected under 35 USC 112(b). Applicant’s amendment to the claim to change dependency from claim 11 to 15 and to remove the optional limitations has overcome the rejection and the rejection is withdrawn.
Claims 19 and 34 were rejected under 35 USC 112(b). Applicant’s amendment to remove the word “preferably”, and the limitations that follow, has overcome the rejections and the rejections are withdrawn.
The following grounds rejections are either maintained or new as necessitated by applicant’s amendment to the claims.
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 1-3, 5-11, 13, 15, 17, 19, 21-22, 24, 29-31, 34, and 41-43 are rejected under 35 U.S.C. 103 as being unpatentable over US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 as evidenced by Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20.
US’193 teaches compositions and methods relating to chemotherapeutic agent conjugates and the treatment of cancer (abstract). US’193 teaches chemotherapeutic agents for use in the conjugates including HSP90 inhibitors (col. 13, line 56 – col. 14, line 20; col. 14, line 11; col. 46, lines 35-45) and that the chemotherapeutics are conjugated to cholesterol (col. 1, lines 58-59), which is a lipid and cholestanoid.
US’193 teaches that the level of a chemotherapeutic agent that is necessary to effectively treat cancer is often well above the level at which dangerous side effects are likely to occur. Therefore, conjugates have been designed which increase the level of chemotherapeutic agent that is delivered to the tumor while reducing the accumulation of the chemotherapeutics in other tissues. These conjugates overcome the difficulties typically encountered with nanoformulation of chemotherapeutic agents, which limit the entrapment efficiency or introduce sub-optimal release kinetics (col. 1, lines 47-56).
US’193 teaches that the conjugate comprises a chemotherapeutic agent conjugated to cholesterol. In some embodiments, the conjugate is an amphiphile. US’193 further teaches that the agent is conjugated to the cholesterol via a linker and discloses linkers which overlap with those of instant claim 8, including C(O), C(O)CH2CH2C(O), or C(O)NH(CH2)2NHC(O)(CH2)2C(O) (col. 1, line 60 – col. 2, line 24). US’193 further teaches that the chemotherapeutic agent and lipid can be covalently conjugated using a reactive functional group present in their respective structures. The term “reactive functional group” refers to a functional group that is capable of reacting with another functional group. Exemplary functional groups include, but are not limited to, hydroxyls, amines, thiols, thials, sulfinos, carboxylic acids, amides, and the like. In some embodiments, the reactive group on the lipid is a hydroxyl, an amine, a thiol, or a carboxylic acid. In some embodiments, the reactive group on the chemotherapeutic agent is a hydroxyl, an amine, a thiol, or a carboxylic acid (col. 11, line 57 – col. 12, line 3)
US’193 further teaches that the term “chemotherapeutic agent” refers to any chemical or biological agent with therapeutic usefulness in the treatment of diseases characterized by abnormal cell growth. Such disease include tumors, neoplasms and cancer, as well as diseases characterized by hyperplastic growth. Chemotherapeutic agents include small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including fragments and/or variants thereof (col. 13, lines 12-46).
US’193 further teaches that the chemotherapeutic agent includes HSP90 inhibitors (col. 46, lines 35-45). The term “HSP90 inhibitors” includes compounds targeting, decreasing, or inhibiting the intrinsic ATPase activity of HSP90; degrading, targeting, decreasing or inhibiting the HSP90 client proteins via the ubiquitin proteasome pathway. Compounds targeting, decreasing or inhibiting the intrinsic ATPase activity of HSP90 are especially compounds, proteins, or antibodies which inhibit the ATPase activity of HSP90, including radicicol, 17-AAG, and geldanamycin derivatives (col. 46, lines 35-45).
US’193 further teaches compositions comprising the conjugate and teaches that the composition can further comprise one or more additional lipids and/or other components, such as cholesterol. US’193 teaches that other lipids can be included for a variety of purposes, such as to prevent lipid oxidation, to stabilize bilayer, to reduce aggregation during formation, or to attach ligands onto the particle surface (col. 21, lines 52-58). Suitable compounds that reduce aggregation include, but are not limited to polyethylene glycol (PEG)-modified lipids, i.e., PEG conjugated lipids. Exemplary suitable PEG-modified lipids include PEG-modified diacylglycerols and dialkylglycerols, PEG-modified posphatidylethanolamine and phosphatidic acid, PEG-ceramide conjugates, PEG-modified dialkylamines, and PEG-modified 1,2-diacyloxypropan-3-amines (col. 22, lines 29-43). US’193 also teaches that the composition further comprises a phospholipid. The phospholipids can be partially purified or fractionated to comprise pure fractions or mixtures of phosphatidyl cholines, phosphatidyl cholines with defied acyl groups having 6 to 22 carbon atoms, phosphatidyl ethanolamines, phosphatidyl inositols, phosphatidic acids, phosphatidyl serines, sphingomyelin, or phosphatidyl glycerols. US’193 also teaches suitable phospholipids that overlap with those that are recited in claim 43 (col. 24, lines 3-41). US’193 teaches that, in some embodiments, the composition comprises the conjugate, a PEG conjugated lipid, and a phospholipid (col. 6, lines 39-40).
US’193 teaches that the composition further comprises an anticancer agent in addition to the conjugate. US’193 further teaches anticancer agents including a platinum compound, an alkylating agent, an anti-metabolite, and paclitaxel, which is a taxane (col. 5, line 56 – col. 6, line 9; col. 17, lines 16-17).
US’193 further teaches pharmaceutical compositions comprising the compositions disclosed and a pharmaceutically acceptable carrier (col. 6, lines 48-50).
US’193 further teaches a method of treating cancer comprising administering a therapeutically effective amount of the compositions to a patient in need of treatment for cancer. In some embodiments, the cancer is selected from the group consisting of: breast cancer, ovarian cancer, glioma, gastrointestinal cancer, prostate cancer, carcinoma, lung carcinoma, hepatocellular carcinoma, testicular cancer, cervical cancer, endometrial cancer, bladder cancer, head and neck cancer, lung cancer, gastro-esophageal cancer, and gynecological cancer (col. 6, lines 51-60; col. 33, lines 37-54).
US’193 further teaches that the method comprises co-administering one or more additional anti-cancer therapies to the patient (col. 6, lines 62-65).
While US’193 does not exemplify a conjugate of a HSP90 inhibitor to a lipid, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to conjugate a HSP90 inhibitor to a lipid, specifically cholesterol, for use in the products, compositions, and methods disclosed by US’193 based on the teachings of US’193 as a whole. A HSP90 inhibitor-lipid conjugate would have been obvious as US’193 teaches chemotherapeutic agent lipid conjugates and teaches HSP90 inhibitors as the chemotherapeutic agent. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Regarding claim 10, as discussed above, US’193 teaches that the HSP90 inhibitor is radicicol (col. 46, lines 35-45). Radicicol has the following structure as evidenced by Sidera (page 6, Fig. (4)):
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As discussed above, US’193 also teaches that the reactive group on the chemotherapeutic agent can be a hydroxyl group (col. 12, lines 1-3).
US’193 exemplifies conjugates in which cholesterol is linked to PI3K inhibitors including the following compound (col. 50, Formula II):
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The compound of Formula II disclosed by US’193 comprises the linker and cholesterol molecule of the instantly claimed compounds as annotated with a box in the formula above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to produce a radicicol-cholesterol conjugate by conjugating the linker and cholesterol molecule exemplified by US’193 to either of the hydroxyl groups on radicicol based on the teachings of US’193 arriving at the claimed conjugates. It would have been obvious to produce the radicicol-cholesterol conjugate in this way as US’193 demonstrates the use of the linker-cholesterol in the formation of conjugate, discloses that the conjugate can comprise the HSP90 inhibitor radicicol, and teaches that hydroxyl groups on the chemotherapeutic agent can be used as reactive groups to covalently conjugate the chemotherapeutic group to the linker/lipid. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 as applied to claims 1 and 3 above, and in further view of Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20.
US’193 teaches the conjugate of claim 3 as discussed in detail above.
US’193, however, does not teach that the HSP90 inhibitor is an analog of radicicol selected from KF25706, KF58333, radester, and pochonin D.
Sidera teaches that HSP90 plays a pivotal role in maintaining transformation and in elevating the survival and growth potential of cancer cells, since its essential chaperoning functions are exploited to facilitate the acquisition and maintenance of the malignant phenotype. As a consequence, HSP90 can frequently be upregulated in tumor cells, in transformed cells, malignancies of the hematopoietic system, and in solid tumors of various entities including ovarian and endometrial carcinomas, as well as in breast, lung, prostate, and gastrointestinal cancers. HSP90 inhibitors lead to degradation of these oncogenic clients and could result in a combinatorial and simultaneous interruption of all of the key alterations upon which cancer cells depend on for their growth and survival. Finally, despite the fact that HSP90 is an abundant protein, HSP90 inhibitors selectively accumulate in tumors rather than in normal tissues, thus destroying tumor cells over normal cells. This therapeutic selectivity of HSP90 inhibitors results from the presence of a predominantly high-affinity, activated form of HSP90 in tumors, whereas HSP90 in normal tissues is in a low-affinity, inactive form (page 3, left column, paragraph 1).
Sidera teaches that the druggability of HSP90 was established using the natural products geldanamycin (GA) and radicicol (RD) (page 3, right column, A1). Sidera further teaches radicicol analogs including KF55823, KF25706, radester, and pochonin D (page 5, right column, A1.2; page 6, Fig. 4).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to substitute the radicicol in the conjugate taught by US’193 with a radicicol analog including KF55823, KF25706, radester, or pochonin D, as taught by Sidera. One of ordinary skill in the art would have been able to make this substitution and the results would have been predictable as Sidera teaches the analog compounds as alternatives to radicicol for use as HSP90 inhibitors for the treatment of cancer. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 44 is rejected under 35 U.S.C. 103 as being unpatentable over US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 as applied to claims 1, 30, and 34 above, and in further view of Caldas-Lopes, E., et al (2009) Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple negative breast cancer models PNAS 106(20); 8368-8373.
US’193 teaches the method of claim 34 as discussed in detail above.
While US’193 teaches the treatment of breast cancer, US’193 does not teach that the breast cancer is triple negative breast cancer (TNBC) as claimed.
Caldas-Lopes teaches that triple negative breast cancers (TNBCs) are defined by lack of expression of estrogen, progesterone, and HER2 receptors. Because of the absence of identified targets and targeted therapies, and due to a heterogeneous molecular presentation, treatment guidelines for patients with TNBC include only conventional chemotherapy. Such treatment, while effective for some, leaves others with high rates of early relapse and is not curative for any patient with metastatic disease. Caldas-Lopes demonstrates that these tumors are sensitive to HSP90 inhibitor, PU-H71. Potent and durable anti-tumor effects in TNBC xenografts, including complete response and tumor regression, without toxicity to the host were achieved. PU-H71 was administered for 5 months without signs of resistance. Caldas-Lopes teaches that, through a proteomics approach, it is shown that multiple oncoproteins involved in tumor proliferation, survival, and invasive potential are in complex with PU-H71 bound HSP90 in TNBC. The HSP90 inhibitor induced efficient and sustained downregulation and inactivation, both in vitro and in vivo, of these proteins. These results identify HSP90 as a critical multimodal target in this most difficult to treat breast cancer subtype (abstract).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by US’193 to treat TNBC as taught by Caldas-Lopes. An ordinarily skilled artisan would have been motivated to treat TNBC as Caldas-Lopes teaches that the disease has been difficult to treat due to the absence of identified targets and targeted therapies and that HSP90 is a critical multimodal target that can be successfully inhibited for the treatment of the disease. Caldas-Lopes also teaches that the use of an Hsp90 inhibitor results in potent and durable anti-tumor effects in TNBC, including complete responses and tumor regression without evidence of resistance over 5 months. An ordinarily skilled artisan would have had a reasonable expectation of success because US’193 teaches HSP90 inhibitor conjugate and teaches the treatment of cancers including breast cancer and Caldas-Lopes teaches the treatment of TNBC with HSP90 inhibitors demonstrating a nexus between the art.
Response to Arguments
Applicant’s arguments in the response filed 03/09/2026 have been fully considered, but are not persuasive.
With regards to the rejections under 35 USC 103, applicant argues that US’193 (referenced by applicant as “Sengupta” in the response) exemplifies cholesterol bonded through a linker to PI-828, PI-103, paclitaxel, and a cisplatin derivative. Applicant argues that these exemplified payloads consist exclusively of PI3K inhibitors, a taxane, and a platinum chemotherapeutic. Applicant argues that HSP90 inhibitors are listed among chemotherapeutic agents which includes nearly every class of chemotherapeutic agent known. Applicant argues that, given that US’193 discloses nearly all chemotherapeutic agents, US’193 discloses a broad genus lacking any motivation or direction to lead an ordinarily skilled artisan to HSP90 inhibitors, or any chemotherapeutics outside of the exemplified payloads.
These arguments are not persuasive.
While US’193 did not exemplify every chemotherapeutic considered conjugated to cholesterol, including HSP90 inhibitors, conclusive proof of efficacy is not required in order to establish a prima facie case of obviousness; rather, the requirement for obviousness is a reasonable expectation of success. MPEP 2143.02 (I) states that “conclusive proof of efficacy is not required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute"))”.
Additionally, explicit motivation in the art is not required in order to establish a prima facie case of obviousness. MPEP 2143 provides 7 exemplary rationales that may be used to support a conclusion of obviousness, KSR (A)-(G), only one of which requires that there be some teaching, suggestion, or motivation in the prior art. In this case, KSR (A), combining prior art elements according to known methods to yield predictable results is applied, a rationale which does not require explicit motivation. As discussed in the rejections, US’193 teaches each of the elements claimed with the only difference being the lack of exemplification. An ordinarily skilled artisan would have been able to combine the elements by known methods and the result of the combination would have been predictable. Specifically, US’193 teaches chemotherapeutics conjugated to cholesterol for the treatment of cancer and teaches that the chemotherapeutic agent can be an HSP90 inhibitor. Therefore, it would have been obvious to arrive at the instantly claimed invention.
Additionally, with regards to applicant’s arguments that US’193 discloses almost all types of chemotherapeutic agents, this alone is not sufficient to establish obviousness. US’193 clearly and distinctly considers HSP90 inhibitors for use in the conjugates (col. 46, lines 35-45). Therefore, one of ordinary skill in the art would have reasonably envisaged conjugates of HSP90 inhibitors with cholesterol using the methods disclosed with a reasonable expectation of success. See MPEP 2131.02 III and MPEP 2144.08.
Applicant further argues that the instant specification demonstrates that, although HSP90 inhibitors alone depressed the function of NK cells against tumor cells due to deactivation of NK cells by HSP90, an HSP inhibitor, radicicol, conjugated to cholesterol selectively targets the tumor and releases the HSP90 inhibitor within the tumor cell, upregulating MICA/B and mouse MULT-1, thereby priming NK recognition resulting in binding of NK to tumor cells and subsequent granzyme mediated apoptosis. Applicant argues that the data demonstrates unexpectedly improved properties that are superior to alternative treatments, specifically unconjugated HSP90 inhibitors for treating cancer. Applicant argues that the existing problem of NK deactivation by HSP90 inhibitors is not demonstrated or expected from the cited references. Applicant cites Examples 1.4, 1.6, and 2.1 for support.
While it is appreciated that applicant has exemplified HSP90 inhibitors, specifically radicicol, conjugated to cholesterol and benefits from such conjugation, applicant has not provided a comparison to the closest prior art in order to demonstrate that the properties of the conjugate are unexpected. In the examples, applicant compares the HSP90-cholesterol conjugate to unconjugated HSP90 inhibitor; however, an unconjugated HSP90 inhibitor is not a closest prior art comparison. In this case, the closest prior art are the conjugates disclosed by US’193.
MPEP 716.02 (b)(III) states “Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims.” MPEP 716.02 (e) states “An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979).”
Additionally, even if the results were identified as being unexpected, which they are not, the results are not commensurate in scope with the instantly claimed invention.
MPEP 716.02(d) states “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.”
Independent claim 1 is drawn to a conjugate comprising any HSP90 inhibitor conjugated by any means to any lipid.
Example 1.4 of the instant disclosure details characterization of 2-in-1 nanomedicines with rapid release of docetaxel and sustained release of the HSP90 inhibitor, radicicol. In the example, radicicol was conjugated to cholesterol using a particular linker (shown in Fig. 4B) and engineered into a nanoparticle comprising both docetaxel and radicicol (pages 75-76).
Example 1.6 studied the use of the DocRad-NPs in reducing tumor burden, in vivo, and in prime residual tumor cells for NK cell surveillance via NKG2D ligand receptor expression (pages 76-77).
Example 2.1 provides the screening of lipid moieties that preferentially target drug tolerant cancer cells (pages 91-92). In the example, an in vitro model of TNBC was exposed to a high dose of docetaxel and cells were based on their capacity to re-adhere after acute population outgrowth. These cells were considered drug tolerant cancer cells. The example then used a lipid-raft targeted screening protocol to identify preferential biding and uptake into DTCCs. Based on the screening, phosphatidylcholine (PC) and cholesterol resulted in significantly increased uptake into DTCCs vs. drug naïve cancer cells (DNCCs), and, to a lesser degree, phosphatidic acid (PA) at levels higher than other lipids. Results are shown in Fig. 8D, which demonstrates that PE, PG, PC, PA, Cholesterol, and PGPE were tested.
The examples of the instant disclosure referenced by applicant in the response tested only a single radicicol-lipid conjugate with a specific linker and demonstrates that this conjugate, when embedded in a DocRad-NP, reduces tumor burden while priming residual tumor cells for NK cell surveillance. As such, the examples that applicant has presented are not commensurate in scope with the claimed invention.
With regards to the rejection of claim 4 under 35 USC 103, applicant argues that Sidera does not remedy the deficiencies of US’193 discussed above.
This argument is not persuasive. Applicant’s arguments concerning US’193 were not persuasive as discussed in detail above. As such, Sidera is not required to remedy ay supposed deficiencies in US’193. Rather, Sidera is applied to demonstrate that the radicicol analogs recited in claim 4 would have been obvious to use in the conjugates of US’193.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
U.S. Patent No. 9,789,193
Claims 1-11, 13, 15, 17, 19, 21-22, 24, 29-31, 34, and 41-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 9,789,193 (herein “9,789,193”) in view of US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 (herein “US’193) and Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20.
9,789,193 claims a composition comprising a conjugate, the conjugate comprising a chemotherapeutic agent conjugated to cholesterol, where the conjugate is of Formula (III):
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9,789,193 further claims that the composition comprises a lipid in addition to the conjugate, that the lipid is conjugated with PEG, and that the PEG conjugated lipid is selected from a group that overlaps with those recited in instant claim 15. 9,789,193 further claims that the composition further comprises a phospholipid including phospholipids that overlap with those recited in instant claim 19. 9,789,193 claims that the composition further comprises a targeting agent and/or an anticancer agent selected from a group which includes paclitaxel (which is a taxane), a platinum compound, an alkylating agent, or an anti-metabolite. The claims of 9,789,193 further include a composition wherein the composition comprises the conjugate, a PEG conjugated lipid, and a phospholipid.
The claims of 9,789,193 differs from the instantly claimed invention in the drug that is conjugated to the cholesterol lipid molecule as well as in the linker that is used to conjugate the drug to the lipid. 9,789,193 also does not claim a method of using the conjugate to treat cancer. These modifications to the claims of 9,789,193, however, would have been obvious in view of the prior art.
The teachings of US’193 and Sidera are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the conjugate in the claims of 9,789,193 by substituting the drug for a HSP90 inhibitor, specifically radicicol, to use a C(O)CH2CH2C(O) linker, and to use the conjugate in a method of treating cancer based on the teachings of US’193. It would have been obvious to substitute the drug in the conjugate with an HSP90 inhibitor as US’193 recognizes HSP90 inhibitors, including radicicol, as alternative chemotherapeutic agents for use in conjugates with cholesterol. It would have been obvious to use a C(O)CH2CH2C(O) linker as US’193 teaches the linker as an alternative to the C(O)NH(CH2)2NHC(O)(CH2)2C(O) linker used in the conjugate of 9,789,193. Thus an ordinarily skilled artisan would have had a reasonable expectation of success.
It would have further been prima facie obvious to one of ordinary skill in the art to substitute the radicicol in the conjugate taught by 9,789,193 modified with US’193 with a radicicol analog including KF55823, KF25706, radester, or pochonin D, as taught by Sidera. One of ordinary skill in the art would have been able to make this substitution and the results would have been predictable as Sidera teaches the analog compounds as alternatives to radicicol for use as HSP90 inhibitors for the treatment of cancer. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 44 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 of U.S. Patent No. 9,789,193 (herein “9,789,193”) in view of US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 (herein “US’193) and Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20 as discussed above, and in further view of Caldas-Lopes, E., et al (2009) Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple negative breast cancer models PNAS 106(20); 8368-8373.
The claims of 9,789,193 modified by US’193 and Sidera teach the method of claim 34 as discussed in detail above.
The combination of 9,789,193, US’193 and Sidera; however, do not teach that the cancer is TNBC.
The teachings of Caldas-Lopes are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the claims of 9,789,193 modified by US’193 and Sidera to treat TNBC as taught by Caldas-Lopes. An ordinarily skilled artisan would have been motivated to treat TNBC as Caldas-Lopes teaches that the disease has been difficult to treat due to the absence of identified targets and targeted therapies and that HSP90 is a critical multimodal target that can be successfully inhibited for the treatment of the disease. Caldas-Lopes also teaches that the use of an Hsp90 inhibitor results in potent and durable anti-tumor effects in TNBC, including complete responses and tumor regression without evidence of resistance over 5 months. An ordinarily skilled artisan would have had a reasonable expectation of success because US’193 teaches HSP90 inhibitor conjugate and teaches the treatment of cancers including breast cancer.
U.S. Patent No. 10,300,143
Claims 1-11, 13, 15, 17, 19, 21-22, 24, 29-31, 34, and 41-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,300,143 in view of US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 and Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20.
US’143 claims a composition comprising a conjugate comprising a chemotherapeutic agent conjugated to cholesterol, wherein the chemotherapeutic agent is a PI3K inhibitor. US’143 further claims that the conjugate comprises the structure of Formula (I) or Formula (II), where Formula (II) has the following structure, which has the same linker and cholesterol structures of the instantly claimed compounds:
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US’143 further claims that the composition further comprises a lipid in addition to the conjugate, that the lipid is conjugated with PEG, as well as PEG conjugated lipids that overlap with instant claim 15. US’143 further claims that the composition further comprises a phospholipid, including phospholipids that overlap with instant claim 19. US’143 further claims that the composition comprises an anticancer agent in addition to the conjugate, including a platinum compound, paclitaxel (which is a taxane), an alkylating agent, or an anti-metabolite. US’143 claims that the composition comprises the conjugate, a PEG conjugated lipid, and a phospholipid. US’143 further claims a method of treating cancer, comprising administering the composition to a subject in need thereof, wherein the cancer is selected from a list that overlaps with instant claim 34.
The claims of US’143 differ from the instantly claimed invention in the drug that is conjugated to the cholesterol lipid molecule which, in the case of US’143, is a PI3K inhibitor, not a HSP90 inhibitor.
The teachings of US’193 and Sidera are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the conjugate in the claims of US’143 by substituting the PI3K inhibitor for a HSP90 inhibitor, specifically radicicol, based on the teachings of US’193. It would have been obvious to substitute the PI3K inhibitor in the conjugate with an HSP90 inhibitor as US’193 recognizes HSP90 inhibitors, including radicicol, as alternative chemotherapeutic agents for PI3K inhibitors for use in conjugates with cholesterol. Thus an ordinarily skilled artisan would have had a reasonable expectation of success.
It would have further been prima facie obvious to one of ordinary skill in the art to substitute the radicicol in the conjugate taught by US’143 modified with US’193 with a radicicol analog including KF55823, KF25706, radester, or pochonin D, as taught by Sidera. One of ordinary skill in the art would have been able to make this substitution and the results would have been predictable as Sidera teaches the analog compounds as alternatives to radicicol for use as HSP90 inhibitors for the treatment of cancer. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 44 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 10,300,143 in view of US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 and Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20 as discussed above, and in further view of Caldas-Lopes, E., et al (2009) Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple negative breast cancer models PNAS 106(20); 8368-8373.
The claims of US’143 modified by US’193 and Sidera teach the method of claim 34 as discussed in detail above.
The combination US’143, US’193 and Sidera; however, do not teach that the cancer is TNBC.
The teachings of Caldas-Lopes are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the claims of US’143 modified by US’193 and Sidera to treat TNBC as taught by Caldas-Lopes. An ordinarily skilled artisan would have been motivated to treat TNBC as Caldas-Lopes teaches that the disease has been difficult to treat due to the absence of identified targets and targeted therapies and that HSP90 is a critical multimodal target that can be successfully inhibited for the treatment of the disease. Caldas-Lopes also teaches that the use of an Hsp90 inhibitor results in potent and durable anti-tumor effects in TNBC, including complete responses and tumor regression without evidence of resistance over 5 months. An ordinarily skilled artisan would have had a reasonable expectation of success because US’193 teaches HSP90 inhibitor conjugate and teaches the treatment of cancers including breast cancer.
U.S. Patent No. 10,426,753
Claims 1-11, 13, 15, 17, 19, 21-22, 24, 29-31, 34, and 41-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10,426,753 in view of US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 and Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20.
US’753 claims a supramolecular combinatorial therapeutic (SCT) comprising a taxane-lipid conjugate, wherein the taxane-lipid conjugate is a cabazitaxel lipid conjugate and has a structure selected from conjugates 1-15 and 21-32. Conjugate 15 of US’753 comprises the following structure which has the same linker and cholesterol structures of the instantly claimed compounds:
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US’753 further claims that the SCT further includes at least one additional lipid, wherein the at least one additional lipid is a phospholipid, where each phospholipid is selected from a group which overlaps with instant claims 15 and 19. US’753 further claims that the SCT comprises a pharmaceutically acceptable carrier. US’753 claims a method of treating cancer comprising administering the SCT optionally along with co-administering one or more additional anticancer therapies to a subject in need of treatment for cancer and claims cancers which overlap with those of instant claim 34. US’753 claims that the composition comprises the conjugate, a first lipid, and a second lipid.
The claims of US’753 differ from the instantly claimed invention in the drug that is conjugated to the cholesterol lipid molecule which, in the case of US’753, is a taxane, not a HSP90 inhibitor.
The teachings of US’193 and Sidera are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the conjugate in the claims of US’753 by substituting the taxane in the conjugate for a HSP90 inhibitor, specifically radicicol, based on the teachings of US’193. It would have been obvious to substitute the taxane in the conjugate with an HSP90 inhibitor as US’193 recognizes HSP90 inhibitors, including radicicol, as alternative chemotherapeutic agents for taxanes for use in conjugates with cholesterol. Thus an ordinarily skilled artisan would have had a reasonable expectation of success.
It would have further been prima facie obvious to one of ordinary skill in the art to substitute the radicicol in the conjugate taught by US’753 modified with US’193 with a radicicol analog including KF55823, KF25706, radester, or pochonin D, as taught by Sidera. One of ordinary skill in the art would have been able to make this substitution and the results would have been predictable as Sidera teaches the analog compounds as alternatives to radicicol for use as HSP90 inhibitors for the treatment of cancer. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 44 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14 of U.S. Patent No. 10,426,753 in view of US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 and Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20 as discussed above, and in further view of Caldas-Lopes, E., et al (2009) Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple negative breast cancer models PNAS 106(20); 8368-8373.
The claims of US’753 modified by US’193 and Sidera teach the method of claim 34 as discussed in detail above.
The combination of US’753, US’193 and Sidera; however, do not teach that the cancer is TNBC.
The teachings of Caldas-Lopes are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the claims of US’753 modified by US’193 and Sidera to treat TNBC as taught by Caldas-Lopes. An ordinarily skilled artisan would have been motivated to treat TNBC as Caldas-Lopes teaches that the disease has been difficult to treat due to the absence of identified targets and targeted therapies and that HSP90 is a critical multimodal target that can be successfully inhibited for the treatment of the disease. Caldas-Lopes also teaches that the use of an Hsp90 inhibitor results in potent and durable anti-tumor effects in TNBC, including complete responses and tumor regression without evidence of resistance over 5 months. An ordinarily skilled artisan would have had a reasonable expectation of success because US’193 teaches HSP90 inhibitor conjugate and teaches the treatment of cancers including breast cancer.
U.S. Patent No. 10,736,968
Claims 1-11, 13, 15, 17, 19, 21-22, 24, 29-31, 34, and 41-43 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10,736,968 in view of US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 and Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20.
US’968 claims a compound of formula I: Xa-Xb-Z-L, where Xa and Xb are as defined and Z is a linker joining Xb with ‘L’, where ‘L’ is a lipid, a lipid derivative or a lipid conjugate or any combination thereof. US’968 further claims linkers that overlap with those of instant claims 8 and 9, and claims that the lipid is selected from a group which includes cholesterol. US’968 claims a formulation comprising the compound of formula I and a phospholipid or a pegylated phospholipid.
The claims of US’968 differ from the instantly claimed invention in the drug that is conjugated to the cholesterol lipid molecule as well as in the additional linker segment that is used to conjugate the drug to the lipid. US’968 also does not claim a method of using the conjugate to treat cancer. These modifications to the claims of US’968, however, would have been obvious in view of the prior art.
The teachings of US’193 and Sidera are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art to modify the conjugate in the claims of US’968 by substituting the drug for a HSP90 inhibitor, specifically radicicol, to use a C(O)CH2CH2C(O) linker, and to use the conjugate in a method of treating cancer based on the teachings of US’193. It would have been obvious to substitute the drug in the conjugate with an HSP90 inhibitor as US’193 recognizes HSP90 inhibitors, including radicicol, as alternative chemotherapeutic agents for use in conjugates with cholesterol. It would have been obvious to use a C(O)CH2CH2C(O) linker as US’193 teaches the linker as an alternative to the C(O)NH(CH2)2NHC(O)(CH2)2C(O) linker used in the conjugate of US’968. Thus an ordinarily skilled artisan would have had a reasonable expectation of success.
It would have further been prima facie obvious to one of ordinary skill in the art to substitute the radicicol in the conjugate taught by US’968 modified with US’193 with a radicicol analog including KF55823, KF25706, radester, or pochonin D, as taught by Sidera. One of ordinary skill in the art would have been able to make this substitution and the results would have been predictable as Sidera teaches the analog compounds as alternatives to radicicol for use as HSP90 inhibitors for the treatment of cancer. Thus, an ordinarily skilled artisan would have had a reasonable expectation of success.
Claim 44 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 10,736,968 in view of US 9,789,193 B3 (Sengupta, S., et al) 17 Oct 2017 and Sidera, K. and E. Patsavoudi (2014) HSP90 inhibitors: current development and potential in cancer therapy Recent patents on anti-cancer drug discovery 9; 1-20 as discussed above, and in further view of Caldas-Lopes, E., et al (2009) Hsp90 inhibitor PU-H71, a multimodal inhibitor of malignancy, induces complete responses in triple negative breast cancer models PNAS 106(20); 8368-8373.
The claims of US’986 modified by US’193 and Sidera teach the method of claim 34 as discussed in detail above.
The combination of US’986, US’193 and Sidera; however, do not teach that the cancer is TNBC.
The teachings of Caldas-Lopes are as discussed in detail above.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to modify the method taught by the claims of US’986 modified by US’193 and Sidera to treat TNBC as taught by Caldas-Lopes. An ordinarily skilled artisan would have been motivated to treat TNBC as Caldas-Lopes teaches that the disease has been difficult to treat due to the absence of identified targets and targeted therapies and that HSP90 is a critical multimodal target that can be successfully inhibited for the treatment of the disease. Caldas-Lopes also teaches that the use of an Hsp90 inhibitor results in potent and durable anti-tumor effects in TNBC, including complete responses and tumor regression without evidence of resistance over 5 months. An ordinarily skilled artisan would have had a reasonable expectation of success because US’193 teaches HSP90 inhibitor conjugate and teaches the treatment of cancers including breast cancer.
Response to Arguments
Applicant’s arguments in the response filed 03/09/2026 have been fully considered, but are not persuasive.
In response to each of the rejections under nonstatutory double patenting, applicant argues that the pending claims cover a conjugate comprising a HSP90 inhibitor conjugated to a lipid and, in light of this and the remarks set forth with respect to the 35 USC 103 rejection, the claims are nonobvious over the cited patents.
Applicant’s arguments concerning the rejections under 35 USC 103 were not persuasive for the reasons discussed in detail above. Therefore, the rejections under nonstatutory double patenting are maintained.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693