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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/30/2025 has been entered.
Applicant’s amendment, filed 9/30/2025, is acknowledged.
Claims 3-7, 10-16, 19-25, 28, 30-46, 48-50, 52-54, 56, 57, 61-64, 66-68, 70-76, 78-85, 88, 91-93, 95-100, 104-108, 110-114, 116-119, 121-142, 145-153, 155-163, 168, 169, 171-175, 177-181, 183-205, and 207-215 are cancelled.
Claims 1, 2, 8, 9, 17, 18, 26, 27, 29, 47, 51, 55, 58-60, 65, 69, 77, 86, 87, 89, 90, 94, 101-103, 109, 115, 120, 143, 144, 154, 164, 165, 167, 170, 176, 182, 206, and 216 are currently pending.
Election/Restrictions
Applicant’s claim amendments, filed 9/30/2025, have amended claims 1, 2, 8, 9, 17, 18, 26, 27, 29, 47, 51, 55, 58-60, 65, 69, 77, 86, 87, 89, 90, 94, 101-103, 109, 115, 120, 143, 144, 154, 164, 165, 167, 170, 176, 182, 206 to recite the unelected species of “hematologic malignancy”.
Claims 1, 2, 8, 9, 17, 18, 26, 27, 29, 47, 51, 55, 58-60, 65, 69, 77, 86, 87, 89, 90, 94, 101-103, 109, 115, 120, 143, 144, 154, 164, 165, 167, 170, 176, 182, 206 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions and/or species.
Claim 216 is under examination.
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Claim Objections
Claims 216 is objected to because the claim recites the acronyms “CXCR4”, “ADRB2”, which are not readily recognized acronyms in the art, such as “DNA” for 5’-deoxyribonucleic acid. Please define the acronyms “CXCR4” and “ADRB2”, when these are first used in the claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 216 is are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Breadth of claims and nature of invention:
Claim 216 encompasses a method of treating glioblastoma comprising administration of burixafor and the elected species of carvedilol.
The specification discloses testing of cancer cells lines, or patient derived cancer cells, for CXCR4/ADRB2 expression, heteromer association in cells, and effects of inhibiting the heteromer (Examples 1-22).
Amount of direction and existence of working examples:
Endogenous expression of CXCR4 and ADRB2, and association of these receptors in a cell, were tested (Examples 6, 7, and 18). Examples 6 and 7 disclose testing for CXCR4/ADRB2 heteromers via proximity ligation assay (PLA) in patient derived glioblastoma cells (Example 6, Fig. 11) and patient derived glioblastoma xenograft samples (Example 7, Fig. 12).
Notably, there is no disclosure in the instant specification of working examples of a method of treating glioblastoma in a subject comprising administration of burixafor and carvedilol.
Applicant has pointed to Example 15 and ¶[00183] as support for (Remarks filed 9/30/2025): “[a] nexus between the suppression of enhanced downstream signaling and inhibition of tumor growth”.
This has been fully considered, however has been found to be not convincing. Example 15 discloses a method of treating A549 lung cancer cells artificially overexpressing CXCR4 and ADRB2 with different CXCR4 inhibitors, including burixafor (Fig. 21D). Notably, this example 1) does not disclose a method of treating a subject with glioblastoma, or with a combination of burixafor and carvedilol; and 2) Fig 21D discloses that there is no significant reduction in tumor progression in subjects after administration with burixafor:
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This is supported by ¶[00182] of the instant specification: “[a]s shown in FIGS. 21A-21D, most of the CXCR4 inhibitors tested showed limited inhibition of tumor growth”.
Additionally, ¶[00183] discloses additional examples of changes in calcium mobilization and changes in cell proliferation resulting from CXCL12 stimulation, however this does not disclose any methods of treating glioblastoma with a combination of burixafor and carvedilol.
Level of predictability, state of prior art, and quantity of experimentation needed:
The instant disclosure and working examples do not disclose a method of treating glioblastoma in a subject comprising administration of burixafor and carvedilol. Additionally, sufficient guidance to enable this method is not found in the prior art. Given the lack of guidance in the prior art and instant specification, undue experimentation would be required by one with ordinary skill in the art to make and use a method of treating glioblastoma in a subject comprising administration of carvedilol and burixafor.
The specification does not reasonably provide enablement to make and use the invention of instant claims 216.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The 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.
Claim 216 is rejected under 35 U.S.C. 103 as being unpatentable over Burman et al. (U.S. Patent No 6,632,832) in view of Gravina et al. (Tumour Biol. 2017 Jun; 39(6): 1010428317695528. doi: 10.1177/1010428317695528) and Hsu et al. (U.S. Patent No. 9,375,406).
Burman et al. teaches using carvedilol in the treatment of glioblastoma (Abstract): “…the invention related to the use of carvedilol for treatment of cancers….glioblastoma…”. Burman et al. teaches (Col. 6, lines 63-67 and Table 2): “[c]arvedilol shows good in vitro cytotoxicity in Human Colon, Ovary, melanoma, Leukemia, Glioblastoma, Prostate, oral and Lung tumor cell lines…”
Burman et al. does not teach CDCR4 antagonists such as burixafor to use in combination with carvedilol in the treatment of glioblastoma.
Gravina et al., in the same field of endeavor, teaches using CXCR4 inhibitors in the treatment of glioblastoma (Abstract). Specifically, Gravina et al. teaches (Introduction):
“The first and most studied CXCR4 antagonist, AMD3100 (Plerixafor), represents a clinically advanced compound and it has been reported to inhibit the growth of GBM and reduce GBM stem cell survival in preclinical studies. AMD3100 is an allosteric agonist of CXCR7, the second SDF1α receptor. AMD31000 also shows elevated cardiotoxicity associated with some other adverse events after long-term usage of drug, prompting the search for new safer and selective CXCR4 inhibitors suitable as anti-GBM agents.”
Thus, Gravina et al. teaches: 1) inhibition of CXCR4 using small molecules such as AMD3100 can successfully inhibit glioblastoma tumor progression; and 2) there is a motivation to try other CXCR4 inhibitors in the treatment of glioblastoma, as the most studied CXCR4 antagonist AMD3100 shows elevated cardiotoxicity.
Gravina et al. does not teach the CXCR4 antagonist burixafor (a.k.a. TG-0054 or GPC100).
Hsu et al., in the same field of endeavor, teaches the CXCR4 inhibitor TG-0054 for use in the treatment of cancer (Abstract, claims 1-10, Compound 5):
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It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to have modified the teachings of Burman et al. in view of Gravina et al. and Hsu et al. to make and use a method of treating glioblastoma in a subject comprising administration of carvedilol and the CXCR4 inhibitor burixafor with a reasonable expectation of success, as all of the references are teaching compounds to be used to treat cancers. One would have been motivated to make this change for the purposes of treating glioblastoma with both carvedilol and a CXCR4 inhibitor combination therapy. It is prima facie obvious to combine two compositions each of which is taught by prior art to be useful for same purpose in order to form third composition that is to be used for very same purpose; idea of combining them flows logically from their having been individually taught in prior art. In re Kerkhoven, 205 USPQ 1069, CCPA 1980. See MPEP 2144.06. In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Additionally, one would have been motivated to use burixafor instead of other CXCR4 inhibitors in the treatment of glioblastoma because Gravina et al. teaches that another well-studied CXCR4 inhibitor AMD3100 has elevated cardiotoxicity in subjects, providing motivation to try other CXCR4 inhibitors such as burixafor that is taught by Hsu et al. Additionally, in absence of evidence to the contrary, the CXCR4 inhibitors taught by Gravina et al. and Hsu et al. are considered art-recognized equivalent CXCR4 inhibitor compounds. See Smith v. Hayashi, 209 USPQ 754 (Bd. of Pat. Inter. 1980) (The mere fact that phthalocyanine and selenium function as equivalent photoconductors in the claimed environment was not sufficient to establish that one would have been obvious over the other. However, there was evidence that both phthalocyanine and selenium were known photoconductors in the art of electrophotography. "This, in our view, presents strong evidence of obviousness in substituting one for the other in an electrophotographic environment as a photoconductor." 209 USPQ at 759.). Thus, it would have been obvious to try a different CXCR4 inhibitor such as burixafor/TG-0054.
The functions recited in the wherein clauses of the claim flow naturally from the teachings of the prior art. (citing Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985 (“The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.”), and Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999) (“[T]he discovery of... a scientific explanation for the prior art's functioning, does not render the old composition patentably new to the discoverer.”)).
An obvious formulation cannot become nonobvious simply by measuring and claiming an activity of the formulation in a particular context, “because ‘[t]o hold otherwise would allow any formulation—no matter how obvious—to become patentable merely by testing and claiming an inherent property.’” Persion Pharm., slip op. at 13 (Fed. Cir. Dec. 27, 2019) (citing Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344, 1354 (Fed. Cir. 2012)); see also Gen. Elec. Co. v. Jewel Incandescent Lamp Co., 326 U.S. 242, 249 (1945) (“It is not invention to perceive that the product which others had discovered had qualities they failed to detect.”).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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.
Claim 216 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims1-18 of U.S. Patent No. 10,709,763 (herein Pat '763, in Office Action mailed 7/31/2025). Although the claims at issue are not identical, they are not patentably distinct from each other.
The invention of instant claim 216 is anticipated by Pat ‘763 for the same reasons set forth in the Office Action mailed 7/31/2025. Briefly, Pat ‘763 claims a method of treating cancer in a subject comprising administration of burixafor and carvedilol, wherein the cancer is a brain cancer (claims 1 and 16), which includes glioblastoma (Col. 78 lines 45-53).
Thus, the invention of claim 216 is anticipated by Pat ‘763.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MAHER M HADDAD/Primary Examiner, Art Unit 1641