DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 November 25, 2024 has been reviewed by the examiner and entered of record in the file.
Claims 1-3 and 5 are amended, and claims 19-20 are newly added.
Status of the Claims
3. Applicant previously elected to pursue the following species:
(1) “AKT inhibitor’ as the anticancer agent in claim 1;
(2) “PI3K inhibitor” as the at least one additional agent as recited in claim 2;
(3) “Ipatasertib” as the sub-species of AKT inhibitor in claim 3;
(4) “Ipatasertib and Rapamycin and Pictilisib” as the combination in claim 5;
(5) “A further therapeutic agent” in claim 11 as the further therapeutic intervention;
(6) “CDK 4/6 inhibitor” as the further therapeutic agent in claim 12; and
(8) “breast cancer” as the species of cancer, claim 15.
4. Claims 17 and 18 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claim 13 is also withdrawn from consideration as directed to non-elected species. The non-elected species of claims 1-12 and 14-16 are also withdrawn from consideration as directed to non-elected species.
5. Claims 1-12, 14-16, 19 and 20 are under examination and are the subject of this office action.
Previous Claim Rejections - 35 USC § 103
6. Claims 1, 4, 6, 7, 9 and 14-16 remain rejected under 35 U.S.C. 103 as being unpatentable over Longo and Di Biase, WO 2015134837 A2, in view of Sarker et al., (Clinical Cancer Research 2014).
Instant claim 1 is directed to a method for treating a patient affected by cancer, (more specifically, breast cancer (claim 15), i.e., a solid cancer (claim 14) resistant to treatment (claim 16)),
comprising subjecting the patient to a reduced caloric intake cycle and at least one anticancer agent, (more specifically the combination of the PI3K inhibitor Pictilisib, with the mTOR inhibitor Rapamycin), wherein said reduced caloric intake cycle provides at most 2100 Kcal per day and consists of a first and a second part,
wherein the first part has a regular caloric intake reduced by 30% to 70%, and the second part has a regular caloric intake reduced by 40 to 97%, and
wherein said first part and/or said second part lasts for a period of 24 to 120 hours (claims 6 and 7), wherein the at least one reduced caloric intake cycle is repeated from 1 to 30 times after respective periods of from 5 to 60 days (claim 9).
7. Longo specifically teaches a murine breast cancer model (4T1) comprising multi-cycle treatment (for a total of three cycles), wherein in each cycle, the mice were subjected to a reduced caloric diet for 48 to 72h (comprising either a short-term starvation (STS) or a fasting mimicking diet (FMD)) and received a daily injection of the anti-cancer agent rapamycin (an mTOR inhibitor), followed by a standard chow diet for 10 days between cycles to recover the bodyweight lost see paragraph [0061]). A cycle of 48 to 72h reads on the limitation of a period of 24 to 120 hours required by claims 6 and 7. Longo teaches that “the steps of administering the reduced caloric diet… and administering of the kinase inhibitor constitute a treatment cycle that can be repeated a plurality of times,” which embraces the recited “first part” and “second part,” required by claim 1 (see paragraph [0043]). The standard diet for 10 days between cycles to recover the bodyweight lost, taught by Longo in paragraph [0061]) reads on the limitation of a respective period of from 5 to 60 days between cycles, required by claim 9. Longo demonstrates the effects of STS and rapamycin, i.e. “[i]n a murine breast cancer (4T1) and murine melanoma (B16) mouse allograft models, it is demonstrated that STS and rapamycin have an additive effect in reducing tumor progression, which confirms that STS potentiates the effects of the mTOR kinase inhibitor rapamycin on cancer cells,” (paragraph [0061], first sentence).
8. Regarding the limitation of a reduction in regular caloric intake of 30%-70% of the first part, and a reduction of 40%-97% in the second part, Longo teaches that “the diet provides no more than 1000 kcal per day, and in particular, no more than 813-957 kcal per day. In a variation, the reduced caloric diet provides from about 100 to 1000 kcal per day to the subject,” (paragraph [0046]). Assuming a 2000 kcal per day regular caloric intake, 1000 kcal per day is a 50% reduction in calories, which meets the limitation of a 30-70% reduction, as well as a 40-97% reduction required by claim 1.
9. As such, Longo teaches the treatment of a patient affected by breast cancer comprising subjecting said patient to a reduced calorie diet and administering an mTOR inhibitor, but does not teach the combined administration of a PI3K inhibitor.
10. Yet, Sarker et al. teaches the administration of the PI3k inhibitor pictilisib to patients affected by breast cancer (see Table 1, page 79), wherein pictilisib was well tolerated and achieved antitumor activity (page 84, right column, second full paragraph).
11. Thus, one of skill in the art would be motivate to subject a patient affected by breast cancer to a reduced calorie diet, and administer to said patient a combination of the known mTOR inhibitor rapamycin with the PI3k inhibitor pictilisib, each having previously demonstrated antitumor activity in breast cancer in order to achieve an additive effect for the treatment of breast cancer in said patient. The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law, please see In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). See also In re Kotzab, 217 F.3d 1365, 1370, 55 USPQ2d 1313, 1317 (Fed. Cir. 2000) (setting forth test for implicit teachings); In re Eli Lilly & Co., 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) (discussion of reliance on legal precedent); In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings). Furthermore, MPEP 2144 teaches that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.
12. Please refer to MPEP 2144.06 “I. COMBINING EQUIVALENTS KNOWN FOR THE SAME PURPOSE” wherein Kerkhoven is specifically referenced:
“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 a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious).
13. And, as stated by the Court in KSR International Co., v. Teleflex Inc., 127 US 1727 (2007), “when a patent ‘simply arranges old elements with each performing the same function it had been known to perform’ and yields no more than one would expect from such an arrangement, the combination is obvious” (quoting Sakraida v. AG Pro, Inc., 425 US 273 (1976); see also: Merck v. Biocraft (874 F.2d 804, 807 (Fed. Cir. 1989), indicating that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands; Sundance, Inc. v. DeMonte Fabricated, Ltd., 550 F.3d 1356 (Fed. Cir. 2008): a claimed invention is obvious is it is a combination of known prior art elements that would reasonably have been expected to maintain their respective properties or functions after they had been combined.
As such, claims 1, 4, 6, 7, 9 and 14-16 are prima facie obvious.
Claim 8 is drawn to claim 6, wherein said first part and/or or said second part lasts for approximately 120 hours.
14. Longo additionally teaches wherein a reduced caloric diet, in particular an FMD, for mammal subjects and in particular humans, substitutes the normal diet of a cancer patient for a period of 5 to 21 days with a 17 day maximum for most patients with frequency to be determined based on the frequency and efficacy of other treatments, with more frequent use needed when other treatments are not effective in cancer treatment (paragraph [0053]).
15. Thus, since the recited process is a well-known process, optimization of result-effective variables of said process, such as duration of reduced caloric intake, would be obvious to one skilled in the art. Changing the weight, purity or other characteristic (i.e., temperature, pressure, etc) of an old process does not render the newer claimed form patentable where the difference in weight, purity or characteristic was inherent, please see In re Cofer (CCPA 1966) 354 F2d 664, 148 USPA 268.
As such, claim 8 is prima facie obvious.
16. Claims 2, 3, 5, 19 and 20 remain/are rejected under 35 U.S.C. 103 as being unpatentable over Longo and Di Biase, in view of Sarker et al, as applied to claims 1, 4, 6, 7, 9 and 14-16, above, further in view of Costa et al., Breast Cancer Research and Treatment (2018).
Claim 1 is addressed in detail, above.
Claim 2, as amended, is drawn to claim 1, and limits wherein an AKT inhibitor is administered in combination with the PI3K inhibitor and the mTOR inhibitor, (more specifically, Ipatasertib and Rapamycin and Pictilisib (claims 3 and 5)).
Claim 19 is drawn to a method for treating a patient affected by cancer, comprising subjecting the patient to a reduced caloric intake cycle and a combination of anticancer agents:
wherein the anticancer agent is a combination of an AKT inhibitor, an mTOR inhibitor and a PI3K inhibitor (more specifically, Ipatasertib and Rapamycin and Pictilisib (claim 20));
and wherein the reduced caloric intake cycle provides at most 2100 Kcal per day and consists of a first and a second part, wherein the first part has a regular caloric intake reduced by 30% to 70% and the second part has a regular caloric intake reduced by 40 to 97%.
17. Longo in view of Sarker et al. teach the treatment of a patient affected by breast cancer comprising subjecting said patient to a reduced calorie diet and administering an mTOR inhibitor and a PI3K inhibitor, but do not teach the combined administration with an AKT inhibitor.
18. However, Longo teaches that the combination of STS/ FMD with kinase inhibitors provides a synergistic pro-death role with inhibitors of kinases (paragraph [0043]), and suggest that the potentiating effect of STS/FMD observed with rapamycin is expected to apply to many different kinase inhibitors used in cancer treatment inhibitors of signaling pathways, including AKT-mTOR (paragraph [0062]).
19. And, Costa et al. discuss targeting the PI3K/AKT/mTOR pathway in the treatment of breast cancer, specifically naming the PI3K inhibitor Pictilisib, the AKT inhibitor ipatasertib and the mTOR inhibitor rapamycin (page 399, right column, second paragraph; page 400, left column, second paragraph; and page 400, left column, last paragraph). While Costa et al. do not disclose a single embodiment comprising the administration of pictilisib, ipatasertib, and rapamycin, in this case, when each species is clearly named, the species claim is anticipated no matter how many other species are additionally named. Ex parte A, 17 USPQ2d 1716 (Bd. Pat. App. & Inter.1990) (The claimed compound was named in a reference which also disclosed 45 other compounds. The Board held that the comprehensiveness of the listing did not negate the fact that the compound claimed was specifically taught. The Board compared the facts to the situation in which the compound was found in the Merck Index, saying that "the tenth edition of the Merck Index lists ten thousand compounds. In our view, each and every one of those compounds is described' as that term is used in 35 U.S.C. § 102(a), in that publication."). Id. at 1718. See also In re Sivaramakrishnan, 673 F.2d 1383, 213 USPQ 441 (CCPA 1982). As such, one of skill in the art would be motivated to combine the kinase inhibitors pictilisib, ipatasertib, and rapamycin in the treatment of breast cancer, and would reasonably predict that in combination, each element merely would perform the same function as it did separately.
As such, claims 2, 3, 5, 19 and 20 are prima facie obvious.
20. Claims 10-12 remain rejected under 35 U.S.C. 103 as being unpatentable over Longo and Di Biase, in view of Sarker et al., as applied to claims 1, 4, 6, 7, 9 and 14-16 above, further in view of Dong et al., (Frontiers in Pharmacology, published March 15, 2021).
Claim 1 is addressed in detail, above.
Claim 10 is drawn to claim 1, additionally comprising administering a further therapeutic intervention to said patient (more specifically, a further therapeutic agent that is a CDK4/6 inhibitor (claims 11-12)).
21. Longo in view of Sarker et al. teach the treatment of a patient affected by breast cancer comprising subjecting said patient to a reduced calorie diet and administering an mTOR inhibitor and a PI3K inhibitor, but do not teach the administration of a CDK4/6 inhibitor.
22. Yet, Dong et al. teach that CDK4/6 inhibitors, such as ribociclib, abemaciclib and palbociclib, have been approved for HR+/ HER2− breast cancer treatment, and additionally teach that, “combining PI3K inhibitors with CDK4/6i has been confirmed to have a synergistic effect to overcome intrinsic and adaptive resistance in multiple studies (Voraetal., 2014; Herrera-Abreuetal., 2016). CDK4/6 and PI3K inhibitors together have been shown to induce breast cancer cell apoptosis in vitro and suppress tumor growth in patient-derived tumor xenograft models (Herrera-Abreuetal., 2016). Additionally, mTORC1/2 inhibition has been shown to inhibit Rb phosphorylation, cyclin D1 expression and E2F-mediated transcription in CDK4/6i-resistant cells (Michaloglou et al., 2018),” (page 9, right column, last two paragraphs- page 10, left column, lines 4-14).
23. As such, one skilled in the art would be motivated to combine a CDK4/6 inhibitor with the PI3K/AKT/mTOR pathway inhibitors taught by Longo and Costa et al. for an additive effect in the treatment of breast cancer in a patient in need thereof.
Thus, claims 10-12 are prima facie obvious.
Response to Arguments
24. Applicant traverses the previous obviousness rejection of claims 1, 4, 6, 7, 9 and 14-16 over Longo and Di Biase, in view of Sarker et al. Claims 2, 3, 5, 19, and 20 are further rejected in view of Costa et al. Claims 10-12 are further rejected in view of Dong et al. Applicant argues the following points:
(i) Applicant again references MPEP 716.02(a)(I), entitled “Greater than Expected Results are Evidence of Nonobviousness,” arguing that this subsection of MPEP is a “way to overcome the rule of MPEP 2144.06(I)” (Applicant’s Remarks, page 8). Applicant argues that combining the administration of both an mTOR kinase inhibitor and a PI3K inhibitor provides unexpectedly superior results, since “it was well known in the art that a reduced calorie intake decreases the activity of both PI3K and mTOR when administered separately” (Applicant’s Remarks, page 9,). Applicant contends that a reduced calorie intake unexpectedly increased the activities of both PI3K and mTOR by an escape pathway, making said inhibitors even more effective.
Applicant argues that historically, a restricted diet or mTOR or PI3k inhibitors lead to acquired resistance, yet the inventors have unexpectedly discovered that the recited combination does not.
25. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's argument that combining the administration of both an mTOR kinase inhibitor and a PI3K inhibitor with a reduced caloric intake provides unexpectedly superior results, the fact that the inventor 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. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). In this case, the combined art of record, Longo in view of Sarker et al. (and Costa et al.), motivate one of skill in the art to treat breast cancer in a patient in need thereof by administering a combination of the known mTOR inhibitor rapamycin with the PI3K inhibitor pictilisib (and the AKT inhibitor ipatasertib), each having previously demonstrated antitumor activity in breast cancer, while subjecting said patient to a FMD, in order to achieve an additive effect for the treatment of breast cancer.
26. And, Longo specifically demonstrates that effects of the combination of STS and rapamycin on breast cancer do not lead to acquired resistance, i.e., “[i]n a murine breast cancer (4T1) and murine melanoma (B16) mouse allograft models, it is demonstrated that STS and rapamycin have an additive effect in reducing tumor progression, which confirms that STS potentiates the effects of the mTOR kinase inhibitor rapamycin on cancer cells,” (paragraph [0061], first sentence).
27. Even if we agreed that the claimed method provided synergistic results, more would be required to show nonobviousness, as synergism is not per se unexpected. See In re Diamond, 360 F. 2d 214, 218 ( CCPA 1966). (“What section 103 requires is ‘unexpected synergism’ ... “ (pg. 216, n.7); “we attribute no magic status to synergism per se since it may be expected or unexpected"” (pg. 218)(emphasis added)).
28. And, according to MPEP 716.02(d), the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." The instant claims do not capture Applicant’s alleged unexpected results of the administration of the combination of PI3K, AKT and mTOR inhibitors under fasting conditions. Furthermore, Applicant demonstrates in the Specification that the most potent results were actually obtained when combining three drugs: Pictilisib, Ipatasertib, and Rapamycin, selective inhibitors of PI3K, AKT and mTOR, with FMD cycles induced cell death in SUM159 cells (i.e., triple negative breast cancer cell line), (see Figures 4b, 4c, 4e, 10c, 10d, 11a, 11b), however these limitations are not presently incorporated into claim 19.
29. Thus, the examiner recommends inserting criticality from the administration of the combination of Pictilisib, Ipatasertib, and Rapamycin to a patient in need thereof for the treatment of breast cancer in said patient, wherein said patient is also subjected to the recited FMD cycles, into the claims.
(ii) Applicant argues that claim 1 has been amended to focus on the “greater than unexpected result” achieved by the claimed method. Regarding the examiner’s reliance of KSR Int’l Co v. Teleflex Inc., Applicant asserts that KSR requires sufficient articulated reasoning with some rational underpinning to support the legal conclusion of obviousness, and cautions against impermissible hindsight.
30. Applicant's arguments have been fully considered but they are not persuasive. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). In view of the combined prior art of record, nothing unobvious is seen in combining the mTOR inhibitor rapamycin with the PI3K inhibitor pictilisib (and the AKT inhibitor ipatasertib) for the treatment of breast cancer in a patient in need thereof, each having previously demonstrated activity against breast cancer, and subjecting the patient to an STS or FMD, such that one skilled in the art would have a reasonable expectation of success in the treatment of said patient.
Conclusion
31. In conclusion, claims 1-20 are present in the application. Claims 13, 17 and 18 are presently withdrawn from consideration. Claims 1-12, 14-16, 19 and 20 are rejected. No claim is currently allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/JANET L COPPINS/Examiner, Art Unit 1628
/CRAIG D RICCI/Primary Examiner, Art Unit 1611