DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Claims 106-120 are pending upon entry of amendment filed on 8/8/23.
The instant application comprises 1 independent claim and the invention relates a pharmaceutical combination comprising a phosphoinositide-3-kinase (PI3K) inhibitor and a PD-L1/TGFβ dual inhibitor wherein the PI3K inhibitor comprises (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one. The specification in p. 73 discloses the compound recited in claim 119 is tenalisib or RP6530 or CN401.
3. Applicant’s IDS filed on 8/8/23, 7/8/24 and 5/13/25 have been acknowledged.
4. The oath filed on 8/8//23 has been acknowledged.
5. 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.
6. Acknowledgment is made of Applicant’s claim for foreign priority based on an CN202110184081.5 filed on 2/10/21.
7. 35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
8. Claims 106-119 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claimed “pharmaceutical combination” is not either process, machine, manufacture or composition of matter. For examining purpose, the combination would be interpreted as “composition”.
9. 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.
10. Claims 117 and 120 are 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 pre-AIA the applicant regards as the invention.
Claim 117 recites an improper Markush group. Claim should recite “selected from the group consisting of A, B and C” and claim 117 is missing a conjunction.
Regarding claim 120, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Further, claim 120 recites the limitation "composition” in line 1. There is insufficient antecedent basis for this limitation in the claim 106. Claim 106 recites “combination”.
11. 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.
12. Claims 106-120 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Specifically, there is insufficient written description to demonstrate that Applicant was in possession of the claimed genus of PI3K inhibitor or PD-L1/TGFβ inhibitors, PD-L1 antibody comprising CDRs set forth in SEQ ID:1-3 comprising amino acid substitutions, additions, eliminations, PD-L1 antibody set forth in SEQ ID NO:4 comprising at least 85%, 90%, 95% or 99% sequence identity, TGFβ inhibitor set forth in SEQ ID NO:6 comprising at least 85%, or one or more amino acid addition, substitution, additions, or functionally active fragment thereof, linker set forth in SEQ ID NO:5 comprising at least 85%, 90%, 95% or 99% or dual PD-L1/TGFβ inhibitor set forth in SEQ ID NO:7 comprising at least 85%, 90%, 95% or 99%, or hydrates or prodrugs of compound (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one.
The guidelines of the Examination of Patent Applications Under the 35 U.S.C. 112, §1 “Written Description” Requirement make clear that if a claimed genus does not show actual reduction to practice for a representative number of species, then the Requirement may be alternatively met by reduction to drawings, or by disclosure of properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicant was in possession of the genus (Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001, see specially page 1106 column 3, MPEP2163).
In The Reagents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412) 19 F.3d 1559, the court held that disclosure of a single member of a genus (rat insulin) did not provide adequate written support for the claimed genus (all mammalian insulins). In this same case, the court also noted:
A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. See Fiers, 984F. 2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen). It is only a definition of a useful result rather than a definition of what achieves that result. Many such genes may achieve that result. The description requirement of the patent statue requires a description of an invention, not an indication of a result that might achieve if one made that invention. See In re Wilder 736 F.2d 1516,1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outline goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”). Accordingly, naming the type of material generally known to exist, in the absence of knowledge as to what that material consist of, is not a description of that material”.
The court has further stated that “Adequate written description requires a precise definition such as by structure, formula, chemical name or physical properties, not a mere wish or plan for obtaining the claimed chemical invention”. Id. At 1566, 43 USPQ2d at 1404 (quoting at 1171, 25 USPQ2d at 1606). Also see (CAFC2002). Enzo-Biochem v. Gen-Probe Fiers, 984 F.2d 01-1230.
The instant claims are drawn to combinations of genus of PI3K inhibitor or PD-L1/TGFβ inhibitors, PD-L1 antibody comprising CDRs set forth in SEQ ID:1-3 comprising amino acid substitutions, additions, eliminations, PD-L1 antibody set forth in SEQ ID NO:4 comprising at least 85%, 90%, 95% or 99% sequence identity, TGFβ inhibitor set forth in SEQ ID NO:6 comprising at least 85%, or one or more amino acid addition, substitution, additions, or functionally active fragment thereof, linker set forth in SEQ ID NO:5 comprising at least 85%, 90%, 95% or 99% or dual PD-L1/TGFβ inhibitor set forth in SEQ ID NO:7 comprising at least 85%, 90%, 95% or 99%, or hydrates or prodrugs of compound (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one. Thus, claims would encompass structurally unrelated proteins, small molecules, DNA or RNA or antibodies. There is no art recognized correlation between structure and function of such classes of the molecules associated with exhibiting the claimed specific functions PI3K inhibitor or PD-L1/TGFβ inhibitors. For example, the specification discloses tumor reduction activities of combination of PI3K inhibitor and PD-L1/TGFβ inhibitors with CN202 and CN401 (note p. 83-93). The instant specification does not disclose a correlation between structure defined by “genus of PI3K inhibitor or PD-L1/TGFβ inhibitors, PD-L1 antibody comprising CDRs set forth in SEQ ID:1-3 comprising amino acid substitutions, additions, eliminations, PD-L1 antibody set forth in SEQ ID NO:4 comprising at least 85%, 90%, 95% or 99% sequence identity, TGFβ inhibitor set forth in SEQ ID NO:6 comprising at least 85%, or one or more amino acid addition, substitution, additions, or functionally active fragment thereof, linker set forth in SEQ ID NO:5 comprising at least 85%, 90%, 95% or 99% or dual PD-L1/TGFβ inhibitor set forth in SEQ ID NO:7 comprising at least 85%, 90%, 95% or 99%, or hydrates or prodrugs of compound (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one”. Further, the disclosed species are not sufficiently representative of the huge genus encompassed by the present claims. Thus, one of skilled in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus of the claimed pharmaceutical compositions. See Eli Lilly, 119 F, 3d 1559, 43, USPQ2d, 1398.
13. Claims 106-120 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for a combination comprising PI3K inhibitor and PD-L1/TGFβ inhibitors, wherein the PI3K inhibitor is (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one or tenalisib and PD-L1/TGFβ inhibitors is SEQ iD NO:7 does not reasonably provide enablement for more.
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use of the invention commensurate in scope with these claims.
The specification does not enable one of skill in the art to practice the invention as claimed without undue experimentation. 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 the skilled in the art to practice the claimed invention.
There is insufficient guidance in the specification as filed as to how the skilled artisan would make and use the genus of PI3K inhibitor or PD-L1/TGFβ inhibitors, PD-L1 antibody comprising CDRs set forth in SEQ ID:1-3 comprising amino acid substitutions, additions, eliminations, PD-L1 antibody set forth in SEQ ID NO:4 comprising at least 85%, 90%, 95% or 99% sequence identity, TGFβ inhibitor set forth in SEQ ID NO:6 comprising at least 85%, or one or more amino acid addition, substitution, additions, or functionally active fragment thereof, linker set forth in SEQ ID NO:5 comprising at least 85%, 90%, 95% or 99% or dual PD-L1/TGFβ inhibitor set forth in SEQ ID NO:7 comprising at least 85%, 90%, 95% or 99%, or hydrates or prodrugs of compound (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one”. Further, the instant specification fails to disclose how to reduce tumor comprising any other genus of PI3K inhibitor or PD-L1/TGFβ inhibitors than (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one or tenalisib and PD-L1/TGFβ inhibitors is SEQ ID NO:7.
Examples 1-4 show how to reduce tumor growth with (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one or tenalisib and PD-L1/TGFβ inhibitors is SEQ iD NO:7 but no other studies have done with functional fragments, unguided amino acid modifications or less than 100% sequence identity to SEQ ID NO:1-7 and a hydrates and prodrugs of tenalisib. The instant specification fails to show the studies encompassing the combinations of functional fragments, unguided amino acid modifications or less than 100% sequence identity to SEQ ID NO:1-7 and a hydrates and prodrugs of tenalisib.
As such, the reduction of tumor growth effect tenalisib and PD-L1/TGFβ inhibitors is SEQ iD NO:7 cannot be extrapolated to any combinations of functional fragments, unguided amino acid modifications or less than 100% sequence identity to SEQ ID NO:1-7 and a hydrates and prodrugs of tenalisib.
To summarize, reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view or the quantity of experimentation necessary, the limited working example, the unpredictability of the art, the lack of sufficient guidance in the specification, and the breath of the claims, it would take undue trials and errors to practice the claimed invention.
14. 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.
15. 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.
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.
16. Claims 106-120 are rejected under 35 U.S.C. 103(a) as being unpatentable over U.S. Pat 9,790,224 in view of U.S. Pub.2017/0022273.
The ‘224 patent teaches compositions comprising (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one or tenalisib in the presence of paclitaxel (col. 7-10, examples). The compound (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one or tenalisib is PI3L δγ inhibitor (col. 5). Further, the ‘224 patent teaches administering antibodies that bind growth factor or receptors thereof (col. 7). The cancers include lymphomas or leukemias (claims 1-32).
The disclosure of the ‘224 patent differs from the instant claimed invention in that it does not teach the use of PD-L1/TGFβ inhibitors or PD-L1/TGFβ inhibitors set forth in SEQ ID NO:1-7 as in claims 106-120 of the instant application.
The ‘273 publication teaches addition of PD-L1/TGFβ inhibitors set forth in SEQ ID NO:4 (note MEDI4736 reads on PD-L1 antibody) and 90% sequence identical to SEQ ID NO:7 (note SEQ ID NO:63-67) (p. 21-22) in treatment of leukemias and lymphomas (claims). The ‘273 publication teaches the use of other chemotherapeutic agent such as paclitaxel in the cancer treatment ([187-196]).
It would have been obvious to one of ordinary skill in the art at the time the invention was made to add PD-L1/TGFβ inhibitors in the forms of antibody as in the ‘273 publication in the composition of (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one or tenalisib taught by the ‘224 patent.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because the addition PD-L1/TGFβ inhibitors in combination cancer therapy would be more effective. It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the 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 the prior art. IN re Kerkhoven, 205 USPQ 1069, CCPA 1980 See MPEP 2144.06.
From the teachings of references, it would have been obvious to one of ordinary skill in art to combine the teachings of the references and there would have been a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of the ordinary in the art at the time of invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
17. 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.
18. Claims 106-120 are rejected on the ground of nonstatutory obviousness- type double patenting as being unpatentable over claims 1-5, 8, 10-12 of U.S. Application Number 17/761127 in view of U.S. Pat. 9,790,224.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘127 application recites a PD-L1/TGFβ antibody set forth in SEQ ID NO:4.
The claims of the ‘127 application differs from the claimed invention in that it does not teach the combination of PI3K inhibitor set forth in claims 106-120 of the instant application.
The teachings of the ‘224 patent have been discussed, supra.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to add a composition of (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one or tenalisib taught by the ‘224 patent in the antibody for PD-L1/TGFβ inhibitors in the forms of antibody in the ‘127 application.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because the addition PD-L1/TGFβ inhibitors in combination cancer therapy would be more effective. It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the 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 the prior art. IN re Kerkhoven, 205 USPQ 1069, CCPA 1980 See MPEP 2144.06.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
19. Claims 106-120 are rejected on the ground of nonstatutory obviousness- type double patenting as being unpatentable over claims 1-19 of U.S. Application Number 17/784617 in view of U.S. Pat. 9,790,224.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of the ‘617 application recites a PD-L1/TGFβ antibody set forth in SEQ ID NO:4.
The claims of the ‘617 application differs from the claimed invention in that it does not teach the combination of PI3K inhibitor set forth in claims 106-120 of the instant application.
The teachings of the ‘224 patent have been discussed, supra.
It would have been obvious to one of ordinary skill in the art at the time the invention was made to add a composition of (S)-2-(1-9H-purin-6-ylamino) propyl group)-3-(3-fluorophenyl)—4H-chromen - - 4- one or tenalisib taught by the ‘224 patent in the antibody for PD-L1/TGFβ inhibitors in the forms of antibody in the ‘617 application.
One of ordinary skill in the art at the time the invention was made would have been motivated to do so because the addition PD-L1/TGFβ inhibitors in combination cancer therapy would be more effective. It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the 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 the prior art. IN re Kerkhoven, 205 USPQ 1069, CCPA 1980 See MPEP 2144.06.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
20. No claims are allowable.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to YUNSOO KIM whose telephone number is (571)272-3176. The examiner can normally be reached Mon-Fri 8:30-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Yunsoo Kim
Patent Examiner
Technology Center 1600
January 30, 2026
/YUNSOO KIM/Primary Examiner, Art Unit 1641