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 . Claims included in prosecution are claims 10 and 12-30.
Previous Rejections
Applicants' arguments, filed 2/19/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
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.
1. Claim(s) 10, 12, 21-22, and 25-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gan et al. (WO 2018108163, Jun. 21, 2018) (hereinafter Gan) in view of Filaggi et al. (US 2018/0265402, Sep. 20, 2018) (hereinafter Filaggi).
Gan teaches pharmaceutical composition containing a PARP inhibitor talazoparib and applications thereof in the treatment of tumors (Abstract). The content of the pharmaceutically active ingredient in the unit formulation before injection is preferably 1-50 mg, and the volume of the single local injection to the human body is preferably 1 mL (satisfies claim 12) (¶ [0020]). The composition has a controllable drug release behavior, after injection, in a predetermined time period (satisfies elutability of claim 10 ). The 24h release amount is preferably less than 20% of the total amount of talazoparib (¶ [0022]). The talazoparib pharmaceutical composition can be used for clinical treatment of tumors such as ovarian cancer, breast cancer, and gastric cancer (satisfies method of claim 10) (¶ [0025]). The composition may be in the form of microspheres, where the drug is dispersed within the polymer matrix (satisfies claim 25). Microspheres have the advantages of high efficiency, non-toxicity, constant release rate, and controllable particle size, and have been widely used in the development of long-acting injections (¶ [0071]). The release rate adjustment polymer matrix material comprises polylactic acid-glycolic acid copolymer (PLGA) (satisfies claim 21-22, & 26) (¶ [0074]). The sustained-release microsphere preparation can be administered intravenously (satisfies delivery via blood vessels of claims 10) (¶ [0076]). In Example 2, talazoparib microspheres were prepared and loaded with 10 mg talazoparib (¶ [0094-0095]). As shown in Fig. 2, about 10% of the talazoparib was released from the microspheres at around 24 hours [FIG. 0002].
Gan differs from the instant claims insofar as disclosing wherein the microspheres lodge at the tumor and form and embolus.
However, Filaggi discloses polyphosphate glass micro spheres which can be loaded with various therapeutic agents (Abstract). Polymeric microspheres are widely accepted as carriers for therapeutic agents due to their excellent biocompatibility and biodegradability (¶ [0004]). Suitable chemotherapeutic agents for use include a PARP inhibitors such as Olaparib, Niraparib (MK-4827), Talazoparib (BMN-673), Veliparib (ABT-888), Rucaparib (AG014699, PF-01367338), CEP 9722, E7016 (Eisai), BGB-290, and 3-aminobenzamide (¶ [0097]). Chemoembolization is a combination of chemotherapy and embolization or embolotherapy, used typically to treat cancer. The addition of chemotherapeutics to inventive microspheres can increase the efficacy of the therapy by improving the timing of exposure of therapy with the terminal embolic effect of the administered microspheres (¶ [0137]). In certain embodiments, blood vessels which nourish a tumor are deliberately blocked by injection of an embolic material into the vessel. Notably, in the case of tumors, vascular occlusion methods can be used to suppress pain, limit blood loss on the surgical intervention to follow embolization, or even bring on a tumoral necrosis and avoid an operation (¶ [0141]).
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application to have formulated the microspheres of Gan to form an embolus at the tumor site and motivated by the desire to achieve higher therapy efficacy, blocking of tumor nourishment, pain suppression, limiting blood loss, tumoral necrosis, and surgical avoidance as taught by Filaggi. One of ordinary skill in the art would have had a reasonable expectation of success since this therapy is a known and effective combination therapy with chemotherapeutics such as talazoparib as taught by Filaggi.
Regarding claim 10 reciting wherein the PARP inhibitor is eluted from the polymer microspheres at a dose ranging from 1-50 mg/day, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). As discussed above, the active agent concentration of Gan’s composition, prior to injection, is preferably 1-50 mg / 1ml. Furthermore, the 24h release amount is preferably less than 20% of the total amount of talazoparib. As such, if the concentration is 50 mg/ml and the release amount is 10% in 24 hrs, that results in a release rate of 5 mg/day. Accordingly, because the range recited in the instant claims overlaps with the release rates disclosed by Gan, the release rates of Gan meet the instantly recited limitations.
Therefore, the combined teachings of Gan and Filaggi render obvious claims 10, 12, 21-22, and 25-27.
2. Claim(s) 13, 15-20, and 28-29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gan et al. (WO 2018108163, Jun. 21, 2018) (hereinafter Gan) in view of Filaggi et al. (US 2018/0265402, Sep. 20, 2018) (hereinafter Filaggi) and further in view of Mikule et al. (US 2020/0306236, Oct. 1, 2020) (hereinafter Mikule).
The teachings of Gan and Filaggi are discussed above.
The combined teachings of Gan and Filaggi differ from the instant claims insofar as not disclosing the use of radiation therapy and the checkpoint inhibitors claimed.
However, Mikule discloses combination therapies containing one or more PARP inhibitors and one or more angiogenesis inhibitor. Mikule also discloses therapeutic uses of such combination therapies useful for preventing tumor cell growth and/or preventing tumor metastasis (Abstract). Suitable PARP inhibitors include talazoparib (¶ [0009]). In some embodiments, the method further comprises administering a third agent to the subject, or performing a therapy such radiotherapy, or a combination thereof (¶ [0065]). Suitable third agents include anti-immunosuppressive agents such as anti PD-1 agent, an anti-PD-LI agent, an anti-CTLA4 agent, an anti-TIM-3 agent, and an anti-LAG-3 agent or any combination thereof (¶ [0067]). Suitable anti PD-1 agents include pembrolizumab (¶ [0068]). In the case of cancer therapy, the amalgamation of anti-cancer drugs can enhance efficacy compared to the monotherapy approach because it can target key pathways in a characteristically synergistic or an additive manner. This approach can potentially reduce drug resistance, while simultaneously providing therapeutic anti-cancer benefits, such as reducing tumor growth and metastatic potential, arresting mitotically active cells, reducing cancer stem cell populations, and inducing apoptosis (¶ [0110]). In some embodiments, the cancer is breast cancer, ovarian cancer, or gastric cancer (¶ [0120]). Suitable anti-TIM-3 agents include antibodies such as MBG453, LY3321367, and TSR-022 (¶ [0197]).
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have modified the method of Gan and Filaggi to further comprise treatment with radiation therapy and/or comprise anti-immunosuppressive agents such as anti PD-1 agent, an anti-PD-LI agent, an anti-CTLA4 agent, an anti-TIM-3 agent, and an anti-LAG-3 agent or any combination thereof, motivated by the desire to achieve an enhanced efficacy in treating cancer as taught by Mikule. One of ordinary skill in the art would have had a reasonable expectation of success since these are effective therapies for use in combination with PARP inhibitors such as talazoparib to treat cancers such as breast cancer, ovarian cancer, and gastric cancer as taught by Mikule.
Regarding claim 28 reciting wherein the PARP inhibitor is eluted from the polymer microspheres at a dose ranging from 1-50 mg/day, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). As discussed above, the active agent concentration of Gan’s composition, prior to injection, is preferably 1-50 mg / 1ml. Furthermore, the 24h release amount is preferably less than 20% of the total amount of talazoparib. As such, if the concentration is 50 mg/ml and the release amount is 10% in 24 hrs, that results in a release rate of 5 mg/day. Accordingly, because the range recited in the instant claims overlaps with the release rates disclosed by Gan, the release rates of Gan meet the instantly recited limitations.
Alternatively, in Example 2, talazoparib microspheres were prepared and loaded with 10 mg talazoparib (¶ [0094-0095]). As shown in Fig. 2, about 10% of the talazoparib was released from the microspheres at around 24 hours [FIG. 0002]. This would result in a talazoparib microsphere where the active is elutable at a dose of about 1 mg/day. Accordingly, because the range recited in the instant claims overlaps with the release rates disclosed by Gan, the release rates of Gan meet the instantly recited limitations.
Therefore, the combined teachings of Gan, Filaggi, and Mikule render obvious claims 13, 15-20, and 28-29.
3. Claim(s) 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gan et al. (WO 2018108163, Jun. 21, 2018) (hereinafter Gan) in view of Filaggi et al. (US 2018/0265402, Sep. 20, 2018) (hereinafter Filaggi) and Mikule et al. (US 2020/0306236, Oct. 1, 2020) (hereinafter Mikule) and further in view of Ure et al. (US 2021/0269479, Sep. 2, 2021) (hereinafter Ure).
The teachings of Gan, Filaggi, and Mikule are discussed above.
The combined teachings of Gan, Filaggi, and Mikule do not specify the type of radiation therapy.
However, Ure discloses methods and compositions suitable for use in preventing and treating proliferative diseases such as cancer (Abstract). The methods and compositions can be used in combination with radiation therapy for inhibiting abnormal cell growth or treating the proliferative disease such as a hyperproliferative disorder. Non-limiting examples of radiation therapy include, but are not limited to, external-beam therapy, internal radiation therapy, and permanent or temporary interstitial brachytherapy (¶ [0265]). Suitable additional actives include PARP inhibitors (¶ [0268]).
Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As discussed above, Gan in view Filaggi and Mikule discloses wherein radiation therapy may be used in combination with treatment with PARP inhibitors such as talazoparib. Accordingly, it would have been prima facie obvious for one of ordinary skill in the art to have modified the method of Gan in view of Mikule to utilize external-beam therapy, internal radiation therapy, and/or brachytherapy, since it is a known radiation therapies for use in inhibiting abnormal cell growth and/or treating a proliferative disease such as cancer as taught by Ure.
Therefore, the combined teachings of Gan, Filaggi, Mikule, and Ure render obvious claim 14.
4. Claim(s) 23-24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gan et al. (WO 2018108163, Jun. 21, 2018) (hereinafter Gan) in view of Filaggi et al. (US 2018/0265402, Sep. 20, 2018) (hereinafter Filaggi) and further in view of Heaysman et al. (US 2018/0250230, Sep. 6, 2018) (hereinafter Heaysman).
The teachings of Gan and Filaggi are discussed above.
The combined teachings of Gan and Filaggi differ from the instant claims insofar as not disclosing the use of crosslinked PVA or wherein the PARP inhibitor is held within the microsphere via ionic interactions.
However, Heaysman discloses polymers that are suitable for the preparation of microspheres. The microspheres are capable of loading and eluting anionic species such as drugs and find use in embolotherapy (Abstract). In embolotherapy, an embolic material is delivered to the blood vessels supplying a tissue, to cause an embolization that prevents or reduces perfusion leading to local tissue necrosis. This approach has gained popularity in the
treatment of vascular tumors. The embolic material is generally delivered as a solid particle. Modern solid embolic materials are typically provided in the form of spherical polymeric particles, known as microspheres (¶ [0002]). The disclosed polymers are suitable for use in embolotherapy, and are capable of loading therapeutically useful quantities of anionically charged molecules, such as drug species and imaging agents and of delivering the drugs in a useful fashion, which have properties making them appropriate for catheter delivery and can be transformed into microspheres using simple and well understood processes (¶ [0008]). The polymer comprises a macromer, the macromer comprising 1,2 or 1,3 dial groups and pendent, cross linkable groups, the pendant cross linkable groups being cross linked (¶ [0009]). PVA (polyvinyl alcohol) comprises 1,3 dial groups and is one example of a suitable polymer for use (¶ [0016]). Polymers and microspheres provided are capable of acting as carriers for a variety
of molecules such as pharmaceutical actives. These molecules may be associated with the polymer in a number of ways, for example by incorporation into the polymer matrix by ionic interaction. The active is releasably bound within the polymer by ionic interactions (¶ [0052]). Particularly the microspheres and polymers may be used with anticancer drugs (¶ [0055]).
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have modified the microsphere of Gan and Filaggi to further comprise PVA and to have the active bound to the microsphere by ionic interaction motivated by the desire utilize polymers that are suitable for use in embolotherapy, and are capable of loading therapeutically useful quantities of drug, and delivering the drugs in a useful fashion, as taught by Heaysman. One of ordinary skill in the art would have had a reasonable expectation of success since this is a known polymer and drug incorporation method for use in polymeric microspheres comprising anticancer agents for use in treating tumors as taught by Heaysman.
Therefore, the combined teachings of Gan, Filaggi, and Heaysman render obvious claims 23-24.
5. Claim(s) 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Gan et al. (WO 2018108163, Jun. 21, 2018) (hereinafter Gan) in view of Filaggi et al. (US 2018/0265402, Sep. 20, 2018) (hereinafter Filaggi) and Mikule et al. (US 2020/0306236, Oct. 1, 2020) (hereinafter Mikule) and further in view of Heaysman et al. (US 2018/0250230, Sep. 6, 2018) (hereinafter Heaysman).
The teachings of Gan, Filaggi, and Mikule are discussed above.
The combined teachings of Gan, Filaggi, and Mikule differ from the instant claims insofar as not disclosing the use of crosslinked PVA.
However, Heaysman discloses polymers that are suitable for the preparation of microspheres. The microspheres are capable of loading and eluting anionic species such as drugs and find use in embolotherapy (Abstract). In embolotherapy, an embolic material is delivered to the blood vessels supplying a tissue, to cause an embolization that prevents or reduces perfusion leading to local tissue necrosis. This approach has gained popularity in the treatment of vascular tumors. The embolic material is generally delivered as a solid particle. Modern solid embolic materials are typically provided in the form of spherical polymeric particles, known as microspheres (¶ [0002]). The disclosed polymers are suitable for use in embolotherapy, and are capable of loading therapeutically useful quantities of anionically charged molecules, such as drug species and imaging agents and of delivering the drugs in a useful fashion, which have properties making them appropriate for catheter delivery and can be transformed into microspheres using simple and well understood processes (¶ [0008]). The polymer comprises a macromer, the macromer comprising 1,2 or 1,3 dial groups and pendent, cross linkable groups, the pendant cross linkable groups being cross linked (¶ [0009]). PVA (polyvinyl alcohol) comprises 1,3 dial groups and is one example of a suitable polymer for use (¶ [0016]). Polymers and microspheres provided are capable of acting as carriers for a variety of molecules such as pharmaceutical actives (¶ [0052]). Particularly the microspheres and polymers may be used with anticancer drugs (¶ [0055]).
Accordingly, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have modified the microsphere of Gan and Filaggi to further comprise PVA motivated by the desire utilize polymers that are suitable for use in embolotherapy, and are capable of loading therapeutically useful quantities of drug, and delivering the drugs in a useful fashion, as taught by Heaysman. One of ordinary skill in the art would have had a reasonable expectation of success since this is a known polymer for use in polymeric microspheres comprising anticancer agents for use in treating tumors as taught by Heaysman.
Therefore, the combined teachings of Gan, Filaggi, Mikule, and Heaysman render obvious claim 30.
Response to Arguments
Applicant’s arguments with respect to claims 10 and 12-30 have been considered but are moot because new rejections necessitated by Applicant’s amendment have been made. As discussed in the current rejections, Gan discloses a talazoparib microsphere where the active is elutable at least at a dose of about 1 mg/day. However, Filaggi’s teaching in reference to chemoembolization and its effects on cancer is applied to meet the requirements of the new limitation “polymer microspheres lodge in the blood vessels to provide an embolus”.
Conclusion
Claims 10 and 12-30 are rejected.
No claims are allowed.
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 Abdulrahman Abbas whose telephone number is (571)270-0878. The examiner can normally be reached M-F: 8:30 - 5:30.
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/A.A./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612