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 .
Priority
This application is a national stage application under 35 U.S.C. § 371 of International
Application No. PCT/US2020/060549, filed 11/13/2020, which claims the priority benefit of
PRO Application No. 62/935,448, filed 11/14/2019.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/12/2022, 06/01/2022,
10/20/2023, 12/01/2023, 10/31/2024, and 11/12/2024 were filed in compliance with the
provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being
considered by the examiner.
The listing of references in the specification (Specification pgs. 30-38) is not a proper
information disclosure statement. 37 CFR l.98(b) requires a list of all patents, publications, or
other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the
list may not be incorporated into the specification but must be submitted in a separate paper."
Therefore, unless the references have been cited by the examiner on form PTO-892, they have
not been considered.
Status of claims
Claims 14, 23, 26, 28, 48, 50-61, and 64-66 are pending. Claims 14, 23, 48, 50, 53, 56-58, 61, and 64-65 have been amended. Claims 1-13, 15-22, 24-25, 27, 29-47, 49, and 62-63 have been cancelled by applicant without prejudice or disclaimer. Claims 14, 23, 26, 28, and 48 have been withdrawn. Claims 50-61 and 64-66 are currently under examination.
Applicant’s arguments, filed 06/23/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. They constitute the complete set presently being applied to the instant application.
The obviousness rejection below is repeated from the 03/23/2026 Office Action and modified in order to address the most recent amendments.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 66 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 66 recites the limitation "whereupon administration to the subject in need thereof," in instant claim 66, line 2. There is insufficient antecedent basis for this limitation in the claim.
Dependent claim 66 is a composition claim dependent on independent claim 50, which is also a composition claim however claim 66 cites the active step of administration of a composition to a subject in need thereof whereas the preamble of claim 66 states “[t]he pharmaceutical composition according to Claim 50”.
Regarding the limitations “whereupon administration to the subject in need thereof”– it is noted that these claims merely recite properties of the anticipated compositions. “Products of an identical chemical composition cannot have mutually exclusive properties.” 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 USPQd 1655, 1658 (Fed. Cir. 1990). Since the prior art teaches a product of identical chemical composition to that claimed, and the application discloses that all of the claimed compositions have the claimed properties, these limitations are also anticipated. Since the prior art teaches the identical chemical structure, the properties applicant claims are necessarily present. In re Spada, 911 F. 2d 705, 709, 15 USPQd 1655, 1658 (Fed. Cir. 1990). Since the prior art teaches a product of identical chemical composition to that claimed, and the application discloses that all of the claimed compositions have the claimed properties and no additional components are claimed (such as an excipient, adjuvant, carrier, etc.), these limitations are also anticipated. The claimed compositions teach a compound of formula (I) and no additional components. Therefore, the claims are anticipated by the aforementioned compounds of formula (I), capable of being used with the claimed intended uses, as described herein.
MPEP 2111.02(II) provides the following instruction for interpreting the preamble of a claim: “During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim.” If a prior art structure is capable of performing the intended use as recited in the preamble, then it meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997). Since the compositions taught by the prior art do not have any structural difference from the claimed compositions and the prior art compositions are capable of the intended uses, those limitations are also anticipated, as discussed herein.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 50-54, 56-59, and 66 are rejected under 35 U.S.C. 102(a)(l) and 102(a)(2) as being anticipated by Rathinavelu (Anti-cancer effects of F16: A novel vascular endothelial growth factor receptor-specific inhibitor).
Rathinavelu teaches the anti-angiogenic drug l,3-dioxo-2,3-dihydro-lH-isoindol-4-yl) amide, named Fl6 used for treating solid tumors by inhibiting angiogenesis through direct binding with VEGFR-2 and it's use in combination with cytotoxic agents including Taxol, a known chemotherapeutic compound (introduction, page 2, 2nd col. Para 1-2). Rathinavelu et al. also teaches the compound of Fl6, administered as a 100 mg/kg dose in combination cancer therapy with the chemotherapeutic compound Taxol in a 10 mg/kg dose to inhibit tumor growth (fig. 7, page 9). The teachings of Rathinavelu anticipate the limitations of a pharmaceutical composition for treatment of delaying progression of brain cancer, delaying intracranial progression of glioblastoma multiforme (GBM), and a brain tumor comprising a therapeutically effective dosage of F16, isoindole (1,3-dioxy-2, 3-dihydro-1H-isoindol-4-yl) amide) and further comprising a pharmaceutical carrier. Claims 51-56 and 66 are dependent on claim 50, claims 58-61 are dependent on claim 57, wherein all claims are drawn to compositions having an intended use rather than method of using type claims. See MPEP 2131.03 Anticipation of Ranges, and MPEP 2111. 02 (II) which states:
“The claim preamble must be read in the context of the entire claim. The determination of whether preamble recitations are structural limitations or mere statements of purpose or use "can be resolved only on review of the entirety of the [record] to gain an understanding of what the inventors actually invented and intended to encompass by the claim" as drafted without importing "‘extraneous’ limitations from the specification." Corning Glass Works, 868 F.2d at 1257, 9 USPQ2d at 1966. If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction…To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997)”
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 50-61 and 64-66 are rejected under 35 U.S.C. 103 as being unpatentable over Rathinavelu (Anti-cancer effects of F16: A novel vascular endothelial growth factor receptor-specific inhibitor) in view of Lee (Combined inhibition of vascular endothelial growth factor receptor signaling with temozolomide enhances cytotoxicity against human glioblastoma cells via downregulation of Neuropilin-1).
The instant claims are directed to a pharmaceutical composition comprising Fl6, isoindole (1,3-dioxy-2, 3-dihydro-1H-isoindol-4-yl)-amide) in a pharmaceutical carrier and the chemotherapeutic agent of temozolomide (TMZ).
Rathinavelu et al. teach the compound of Fl6, administered as a 100 mg/kg dose in combination cancer therapy with the chemotherapeutic compound Taxol in a 10 mg/kg dose to inhibit tumor growth (fig. 7, page 9). Rathinavelu also teaches that compound Fl6 exerts inhibitory effects on angiogenesis and anti-angiogenic therapy and has added value to traditional chemotherapy for solid tumors due to the suppression of tumor invasion and metastasis by inhibiting VEGF-driven migration of endothelial cells (pg. 9, col. 1). Rathinavelu discloses the role VEGFR-2 and PAK have on human gliomas and discloses Fl6 influences a decline in p- FAK level associated with the rapid dissolution of cell (cytoskeletal) integrity, disintegration of cell adhesion molecules and initiation of cell migration and related events such as metastasis in cancer cells (page 10, col. 2).
However, Rathinavelu et al. fails to disclose temozolomide as the additional chemotherapeutic administered in a 50 mg/kg per body weight dose.
Lee et al. teach synergistic action of temozolomide (TMZ) and anti-VEGF therapy in GBM cells in four human GBM cell lines: TMZ-sensitive U25l-MG and U373-MG cells, and TMZ-resistant CRT-MG and LN2l5- MG cells, and that treatment of TMZ along with a sublethal dosage range of SU1498, a chemical inhibitor of the VEGF receptor signaling, induced significant cell death in both TMZ-sensitive and TMZ-resistant GBM cells without changing the status of the MGMT promoter methylation (Abstract). Lee discloses "TMZ can be orally administered with excellent bioavailability and efficiently crosses the blood-brain barrier. Due to its favorable pharmacokinetic properties, TMZ is used as an effective chemotherapeutic agent against primary brain tumors including GBM. In the present study, we investigated the synergistic action and its molecular mechanism of TMZ and VEGF antagonists in human GBM cells to test the potential use of VEGF antagonists as adjuvant options for overcoming the resistance to TMZ treatment" (Introduction, pg. 29-30).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to combine the use of a TMZ and VEGF inhibitor in a composition for the treatment of GBM as disclosed by Lee wherein a skilled artisan would select the VEGFR inhibitor compound of Fl6 disclosed by Rathinavelu because Fl6 demonstrated synergistic effects when combined with TMZ, specifically the desirable property of overcoming the resistance in TMZ treatment.
Regarding the limitations "composition" and "pharmaceutical" - it is noted that these claims merely recite properties of the anticipated compounds. "Products of an identical chemical composition cannot have mutually exclusive properties." Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911F. 2d 705, 709, 15 USPQd 1655, 1658 (Fed. Cir. 1990). Since the prior art teaches a product of identical chemical composition to that claimed, and the application discloses that all of the claimed compositions have the claimed properties, these limitations are also anticipated. Since the prior art teaches the identical chemical structure, the properties applicant claims are necessarily present. In re Spada, 911 F. 2d 705, 709, 15 USPQd 1655, 1658 (Fed. Cir. 1990). Since the prior art teaches a product of identical chemical composition to that claimed, and the prior art discloses that all of the claimed compositions have the claimed properties and no additional components are claimed (such as an excipient, adjuvant, carrier, etc.), these limitations are also anticipated. Therefore, the claims are anticipated by the aforementioned compounds, capable of being used with the claimed intended uses of “composition” and “pharmaceutical” as described herein.
MPEP 2111. 02(11) provides the following instruction for interpreting the preamble of a claim: "During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether the recited purpose or intended use results in a structural difference ( or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim." If a prior art structure is capable of performing the intended use as recited in the preamble, then it meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997). Since the compositions taught by the prior art do not have any structural difference from the claimed compositions and the prior art compositions are capable of the intended uses, those limitations are also anticipated, as discussed herein. As such, the claims are directed to the same invention.
A person of ordinary skill in the art would have been motivated to administer the
compound of Fl 6 to a subject in need thereof for its effects on cancer angiogenesis, VEGF and
the favorable results of a combination therapy with a chemotherapy agent based on the
disclosures of Rathinavelu, specifically Rathinavelu's teachings of VEGF receptors as targets in
the treatment of glioblastomas would have further reinforced the motivation, especially in light
of Lee's disclosures of a combination therapy with TMZ and other standard treatments of
glioblastoma including VEGF inhibitors. A person of ordinary skill would have had a reasonable
expectation of success in treating glioblastoma from the cumulative effects of combining two
compounds known in the prior art which are used for the same purpose. Therefore, the disclosure
as a whole is prima facie obvious to one of ordinary skill in the art at the time the application was filed based on the current record. See also MPEP 2144.06, MPEP 2112.01 (I and II) and
2111.02(II).
Response to Arguments
Applicant's arguments filed 06/23/2026 have been fully considered but they are not persuasive.
Applicant’s arguments rely on language solely recited in preamble recitations in claim(s) 50-61 and 64-66. When reading the preamble in the context of the entire claim, the recitation “for delaying progression of brain cancer" in claim 50 (and similar language in claim 57)” is not limiting because the body of the claim describes a complete invention and the language recited solely in the preamble does not provide any distinct definition of any of the claimed invention’s limitations. Thus, the preamble of the claim(s) is not considered a limitation and is of no significance to claim construction. See Pitney Bowes, Inc. v. Hewlett-Packard Co., 182 F.3d 1298, 1305, 51 USPQ2d 1161, 1165 (Fed. Cir. 1999). See MPEP § 2111.02.
The examiner notes that the applicants claim of preamble language of “The preamble language "for delaying progression of brain cancer" in claim 50 (and similar language in claim 57) is not merely a statement of intended use-it defines the therapeutic context that gives meaning to the term "therapeutically effective dosage."” in the reply (pg. 13, last para.) is a limitation of the claims, wherein the instant claim preambles are “pharmaceutical composition” not “for delaying progression of brain cancer" (reply pg. 13, 2nd para), as the applicant alleges.
In response to applicant's argument that “formulated for penetration of the blood brain barrier (BBB) and delaying progression of brain cancer, specifically delaying intracranial progression of glioblastoma multiforme”, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
Examiner notes the requirements for applicants claimed pharmaceutical composition are 1) a compound of F16 (isoindole (1,3-dioxy-2, 3-dihydro-lH-isoindol-4-yl)-amide)) and 2) a chemotherapeutic agent. Claims for a method of treating are not currently under examination, see restriction/election office action dated 01/24/2025, wherein Group II, claims 14, 23, 26, 28-29, and 48 were withdrawn from examination by applicants election in reply dated 03/24/2025. Therefore, the 35 U.S.C. 102(a)(l) and 102(a)(2) rejection is met by the prior art of Rathinavelu (Anti-cancer effects of F16: A novel vascular endothelial growth factor receptor-specific inhibitor) alone wherein a compound of F16 (isoindole (1,3-dioxy-2, 3-dihydro-1H-isoindol-4-yl)-amide)) and the chemotherapeutic agent (Taxol) are disclosed in a composition.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
A skilled artisan would have combined Rathinavelu’s teachings of F16 with Lee’s disclosure of temozolomide (TMZ) because Rathinavelu disclosed cancer treatments with F16 “Thus, F16 offers a promising anti-proliferative and anti-angiogenic effects with better specificity than some of the existing multi-kinase inhibitors.” (abstract) Rathinavelu also discloses “In addition to being effective and safe during monotherapy, F16 was working very well in combination with cytotoxic agents such as Taxol” (pg. 2, right hand col. , 2nd para.) A skilled artisan would have noted cytotoxic agents were not limited to taxol in Rathinavelu and that considering Lee’s disclosure of synergy with TMZ and a kinase inhibitor SU1498 would lead to a reasonable expectation of success in treating glioblastoma multiforme (GBM) See MPEP 2144.06.
Furthermore, applicant argues “Rathinavelu discloses the combination of F16 with Taxol but does not disclose combination of (F16) with temozolomide (TMZ) or any other chemotherapeutic agent.” Examiner notes Rathinavelu indeed discloses the combination of F16 with a chemotherapeutic agent, specifically “The F16 also works very efficiently with Taxol in combination by limiting the tumor growth that is better than the monotherapy with any one of the drugs that were tested individually.” (abstract) and “In addition to being effective and safe during monotherapy, F16 was working very well in combination with cytotoxic agents such as Taxol that is commonly used for effective control of the tumors when anti-angiogenic therapeutics such as Avastin® and Sutent® are used for increasing the overall survival (OS) rate or progression-free survival (PFS) of the patients.” (pg. 2, right col. 2nd para.)
Applicant also argues the original specification demonstrates the ability of F16 to cross the BBB. Pharmacokinetic studies revealed accumulation of F16 in organs of mice following a single dosage of F16 with the unexpected finding that Fl6 concentration at 12 hours post injection was the highest in the brain as compared to accumulation in the liver and kidneys. This finding indicates that F 16 is easily transported across the BBB and accumulated in the brain without evidence of toxicity. See paragraphs [0007] and [0026] and FIG. 2 of the published application. Rathinavelu does not disclose or suggest this BBB-crossing capability, which is essential to brain cancer treatment.
Examiner notes the unexpected finding that Fl6 concentration at 12 h post injection was the highest in the brain compared to liver and kidneys was disclosed in US PAT. 7,939,557 (Specification, lines 5-20), and therefore F16’s ability to cross the blood brain barrier (BBB) is an inherent property of the compound. See MPEP 2112.01 I-III.
Conclusion
All claims 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.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNESTO VALLE JR whose telephone number is (703)756-5356. The examiner can normally be reached 0730-1700 M-F EST, 1st Friday off.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C Milligan can be reached at 571-270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/E.V./
Examiner, Art Unit 1623
/SAMANTHA L SHTERENGARTS/Primary Examiner, Art Unit 1623
