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 371 of PCT/EP2021/060341, filed Apr. 21, 2021 and claims foreign priority to IT102020000008710, filed Apr. 23, 2020 in the Italian Republic.
Claim Status – Response to Restriction/ Election Requirement
Claims 17-37 are pending. Applicant’s election without traverse of Group I, claims 17-36, and the species tamoxifen and palbociclib, in the reply filed on Jan. 5, 2026 is acknowledged. The Applicant failed to identify the claims reading on the elected species. The examiner submits that claims 17-19, 22-30, and 35 encompass the elected invention.
Claims 17-19, 22-30 and 35 are currently active and subject to examination. Claims 20-21, 31-34, and 36-37 are withdrawn.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The specification is objected to as failing to provide proper antecedent basis for the claimed subject matter. See 37 CFR 1.75(d)(1) and MPEP § 608.01(o). Correction of the following is required: Claim 26 recites “a high content of monounsaturated and polyunsaturated fats and a reduced content of proteins and carbohydrates (> 50% of the calories coming from said fats).” The specification only provides support for “a high content of monounsaturated and polyunsaturated fats and a reduced content of proteins and sugars (>40% of calories coming from fat).” (Specification, p. 2, 5).
Claim Rejections – 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
“A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.”
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 17-19, 22-30 and 35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Nencioni et al. (WO 2017/140641 A1) (of record, IDS cite no. 1) in view of Portman et al. (Endocrine-Related Cancer, Vol. 26, Issue 1, p. R15-R30, Jan. 2019).
Claim 17 is directed towards a method of treating breast cancer (BC) or other estrogen- responsive tumors in a human patient with a therapeutic combination of a compound having antiestrogenic activity and a CDK4/6 inhibitor, wherein the method comprises subjecting said patient to reduced calorie intake for a period of 24-190 hours while said patient is being treated with said therapeutic combination.
Nencioni teaches a method of treating BC or other estrogen-responsive tumors in a human patient comprising administering to the patient a compound having antiestrogenic activity and subjecting the patient to reduced caloric intake for a period of 24-190 hours while the patient is being treated with the compound having antiestrogenic activity (Nencioni, Specification, p. 3, lines 27-32).
The method of Nencioni particularly relates to subjecting the patient a “fasting-mimicking diet” (FMD) (Nencioni, Specification, p. 2-3). FMDs are commonly known in the art to sensitize cancer cells to anti-cancer treatments, as well as protect patients from treatment side effects (id.).
Nencioni demonstrates that FMDs increase the efficacy of antiestrogenic therapies and reduce resistance to antiestrogenic therapies by inhibiting the PI3K and mTOR pathways:
The Applicants performed several experiments to assess whether fasting mimicking conditions or a fasting-mimicking diet (1% fetal calf serum and 50 mg/dl glucose - FMD) would sensitize BC cells to tamoxifen and to fulvestrant. Indeed, a strong potentiation of tamoxifen activity by FMD conditions (Figure 1A-C) was detected in all of the cellular models of ER- positive BC tested (MCF7, ZR-75- 1 , T47D)…
The Applicant subsequently investigated the effects of tamoxifen, fasting mimicking conditions or of a fasting-mimicking diet, and their combination on cell signaling, focusing in particular on the PI3K-mTOR pathway given its role in resistance to hormonal treatments in BC [2], [5]. Here it was of interest to observe that combining tamoxifen with fasting mimicking conditions or a fasting-mimicking diet (FMD) resulted in a marked inhibition of mTOR activity as detected by the reduced levels of phosphorylated p70S6K and eIF4E in MCF7, ZR-75- 1 , and T47D (Figure 3). In the experiment of Fig. 3, MCF7, ZR-75- 1 and T47D cells were treated as in the experiment of Figure 2. 24 h after tamoxifen (5 μΜ) addition, cells were used for protein lysate generation and total and phosphorylated p70S6K (Thr389), total and phosphorylated 4E-BP1 , phosphorylated eIF4E (Ser209), HER2 and β-actin were detected by immunoblotting.
In the case of 4E-BP1 (a repressor of mRNA translation that is typically phosphorylated by mTOR, with consequent dissociation of 4E-BP1 from eIF4E and activation of cap-dependent mRNA translation), a marked accumulation of the unphosphorylated form in response to combined tamoxifen and fasting mimicking conditions or a fasting-mimicking diet (FMD) in all of the ER-positive cell lines was detected, which again is in line with impaired mTOR signalling.
Overall, these findings suggested that a block in protein translation may contribute to the strong anticancer activity of combined tamoxifen and fasting mimicking conditions or a fasting-mimicking diet (FMD).
In subsequent experiments, it was also evaluated whether addition of fasting mimicking conditions or a fasting-mimicking diet (FMD) to tamoxifen would affect the expression of HER2, whose upregulation has been implied as a mechanism of resistance to hormonal treatments in BC [2].
Noteworthy, in two out of three BC cell lines (ZR-75- 1 , and T47D), fasting mimicking conditions or a fasting-mimicking diet (FMD) led to a marked reduction in HER2 expression when applied in combination to tamoxifen (Figure 3). Since HER2 signaling helps ER-positive BC cells resist hormone therapy, such an effect of fasting mimicking conditions or a fasting- mimicking diet (FMD) could well contribute to enhance BC cell susceptibility to hormone therapy itself [2].
Nencioni, Specification, p. 11-13 (emphasis added);
Based on these data, initial proof-of-concept (PoC) experiments in MCF7 xenografts were performed to determine whether short course of fasting (48 hours, water only, once a week) would have anticancer activity per se and, most importantly, whether they would potentiate the activity of tamoxifen and of fulvestrant in vivo.
Consistent with the in vitro data, both tamoxifen and cycles of fasting reduced the growth of MCF7 xenografts (Figure 8A, B). However, when combined, the two treatments were significantly more effective than either type of treatment alone…
Overall, the above experimental results clearly demonstrate the ability fasting or a fasting-mimicking diet to increase the activity of commonly prescribed hormone therapies for BC, to downregulate ERa in BC cells, and to counter several known mechanisms of hormone therapy resistance. In addition, they clearly demonstrate how combining a hormone treatment with metabolic conditions resulting from fasting or from a fasting- mimicking diet leads to a major impairment in the DNA repair apparatus of cancer cells, sensitizing them to chemotherapeutics.
Thus, a reduced caloric intake through fasting or through a fasting- mimicking diet represents a new approach for increasing the activity of hormonal treatments, for avoiding (or at least markedly delaying) resistance to these agents and, possibly, for preventing tumor-re-growth or for completely eradicating tumor cells when simultaneously applied with hormonal treatments with or without chemotherapy.
Nencioni, Specification, p. 15-16 (emphasis added).
As shown in the paragraph above, Nencioni teaches that FMD could be simultaneously combined with hormonal treatments with or without chemotherapy. Nencioni also teaches that CDK4/6 inhibitor therapies such as palbociclib also serve to “improve the effect of hormone therapy in BC and/or reinstate the activity of these hormone drugs once resistance has appeared” (Nencioni, Specification, p. 7, lines 11-15).
While Nencioni suggests combination treatment with FMD, antiestrogenic therapy, and chemotherapy and does not explicitly teach combination treatment with FMD, antiestrogenic therapy, and a CDK4/6 inhibitor, one of ordinary skill in the art would have a reasonable expectation of success to combine FMD, antiestrogenic therapy and a CDK4/6 inhibitor because it is commonly known in the art that CDK4/6 inhibitors synergize with antiestrogenic therapy and improve survival, and that CDK4/6 and antiestrogenic therapy resistance may be treated by inhibiting the PI3K-mTOR pathway.
For example, Portman teaches that the combination of CDK4/6 inhibitors and endocrine therapy is the new standard of care in some countries, and have demonstrated benefits in human BC patients:
Three inhibitors of CDK4/6 kinases were recently FDA approved for use in combination with endocrine therapy, and they significantly increase the progression-free survival of patients with advanced estrogen receptor-positive (ER+) breast cancer in the first-line treatment setting. As the new standard of care in some countries, there is the clinical emergence of patients with breast cancer that is both CDK4/6 inhibitor and endocrine therapy resistant. The strategies to combat these cancers with resistance to multiple treatments are not yet defined and represent the next major clinical challenge in ER+ breast cancer. In this review, we discuss how the molecular landscape of endocrine therapy resistance may affect the response to CDK4/6 inhibitors, and how this intersects with biomarkers of intrinsic insensitivity. We identify the handful of pre-clinical models of acquired resistance to CDK4/6 inhibitors and discuss whether the molecular changes in these models are likely to be relevant or modified in the context of endocrine therapy resistance. Finally, we consider the crucial question of how some of these changes are potentially amenable to therapy.
Portman, Abstract;
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Portman, p. R17;
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Portman, p. R19.
Portman teaches that targeting growth factor signaling pathways, such as the PI3K-mTOR signaling pathway, can help to treat resistance to CDK4/6 inhibitors and to combination treatment with antiestrogenic therapy:
CDK4/6 inhibition results in an immediate and profound G0/G1 cell cycle arrest in Rb+ cells (Fry et al. 2004), but in some cancer models, this wanes within several days. This ‘adaptive response’ is postulated to play a role in the acquisition of resistance or at least in the durability of therapeutic response. In ER+ breast cancer cell lines acutely exposed to palbociclib, cell cycle inhibition was temporary; Rb phosphorylation and markers of S phase entry returned within 72 h of first exposure, including increased expression of cyclin D1 (Herrera-Abreu et al. 2016). Non-canonical complexes of cyclin D1 and CDK2 were observed and proposed to be the cause of continued Rb phosphorylation. Increased CDK2 activity was also observed in acute myeloid leukaemia cells after 96 h of palbociclib treatment, and in this model, the increase in CDK2 activity correlated with a decrease in the p27Kip1 inhibitor protein (Wang et al. 2007).
Interestingly, combination therapies have been shown to inhibit this adaptive response. In breast cancer cells, the addition of a PI3K inhibitor to palbociclib delayed the resumption of S phase entry and abrogated the accumulation of cyclin D1, consistent with the role of the PI3K pathway in promoting cyclin D1 expression (Herrera-Abreu et al. 2016). In an independent study, mTOR pathway inhibition synergised with CDK4/6 inhibition to prevent resumption of proliferation of breast cancer cells, and the combination therapy induced a significant downregulation of E2F target genes (Michaloglou et al. 2018). Finally, endocrine therapy co-treatment with CDK4/6 inhibitors is able to suppress the activation of cell metabolism and cell growth in breast cancer cells (Knudsen & Witkiewicz 2016).
Portman, p. R21-R22;
The clinical efficacy of endocrine therapy doublet combination therapy with mTOR, PI3K, and CDK4/6 inhibitors (Baselga et al. 2012, Finn et al. 2015, Cristofanilli et al. 2016, Finn et al. 2016, Baselga et al. 2017, Goetz et al. 2017, Sledge et al. 2017, Slamon et al. 2018), and the cross talk between these pathways (Fig. 2), have led to the logical development of clinical trials of triplet therapy combinations of CDK4/6 and PI3K pathway inhibitors with an endocrine therapy backbone (Table 3). Further supporting this strategy is data that has demonstrated that CDK4/6 inhibitors can sensitize PIK3CA mutant tumours to PI3K inhibitors (Vora et al. 2014), and the converse, that CDK4/6 resistant cells have been shown to be sensitive to mTORC1/2 inhibition (Michaloglou et al. 2018). Finally, combined targeting of CDK4/6 and PI3K pathways resulted in greater tumour regression compared with PI3K or CDK4/6 inhibition alone; and triplet therapy with CDK4/6 and PI3K inhibitors was more effective than dual therapy with respect to tumour regression (O’Brien et al. 2014, Herrera-Abreu et al. 2016). In two recent studies, cohorts of heavily pre-treated patients who had received everolimus obtained limited benefit from the addition of palbociclib, suggesting that CDK4/6 inhibitors should be used prior to or concurrently with drugs targeting the PI3K pathway (Dhakal et al. 2018, du Rusquec et al. 2018). The multiple types of PI3K inhibitors in clinical development, combined with the three lead CDK4/6 inhibitors, multiple classes of ER-directed therapies, and next generation selective ER degraders, in different lines of therapy, have resulted in a large number of combinations and permutations, creating a challenge when determining the optimal therapeutic strategy for a given patient. Further complicating matters are the potential for overlapping toxicity and financial implications.
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Portman, p. R24 (emphasis added).
In summary, Nencioni teaches a method of treating patients with breast cancer (BC) or other hormone dependent cancers, comprising administering to the patient an antiestrogenic agent and subjecting the patient to reduced calorie intake for a period of 24-190 hours while the patient is being treated with the antiestrogenic agent. Nencioni teaches that such fasting mimicking diets (FMDs), increase the efficacy of antiestrogenic agents and chemotherapies, while alleviating side effects of such agents and therapies. Nencioni also teaches that FMDs can reduce resistance to antiestrogenic agents by inhibiting the PI3K and mTOR pathways. Nencioni also suggests that the FMD/antiestrogenic therapy could be conducted simultaneously with additional anti-cancer therapies. While Nencioni does not explicitly teach that the additional anti-cancer therapy is a CDK4/6 inhibitor, one of ordinary skill in the art would have a reasonable expectation of success to add a CDK4/6 inhibitor to the method of Nencioni because (1) the combination of antiestrogenic agents with CDK4/6 inhibitors can be considered standard of care for the treatment of some breast cancers and (2) it is well known that resistance to CDK4/6 inhibitor and antiestrogenic agent combination therapy can also be overcome by inhibition of the PI3K/mTOR pathways, as shown by Portman.
Therefore, claim 17 was prima facie obvious at the time of filing.
Claim 18 is directed towards the method of claim 17, wherein said compound having antiestrogenic activity is selected among the group consisting of selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs) and aromatase inhibitors (Ais).
Nencioni teaches that compounds having antiestrogenic activity include selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs) and aromatase inhibitors (Ais): “By the expression "compounds having antiestrogenic activity" the following compounds are meant: SERMs, SERDs, and AIs.” (Nencioni, Specification, p. 3, lines 18-20).
While Nencioni does not teach SERMs, SERDs and AIs in combination with CDK4/6 inhibitors, one of ordinary skill in the art would have a reasonable expectation of success to combine SERMs, SERDs and Ais with CDK4/6 inhibitors because these are well known combination regimens.
For example, Portman teaches CDK4/6 inhibitors in combination with tamoxifen (SERM), letrozole (AI), and/or fulvestrant (SERD) (Portman, Table 2, p. R19).
Therefore, claim 18 was prima facie obvious at the time of filing.
Claim 19 is directed towards the method of claim 18, wherein the compound having antiestrogenic activity is a SERM and is selected among the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, ospemifene, arzoxifene and bazedoxifene.
As shown above in the rejection of claims 17-18, both Nencioni and Portman teach tamoxifen.
Therefore, claim 19 was prima facie obvious at the time of filing.
Claim 22 is directed towards the method of claim 17, wherein said CDK4/6 inhibitor is selected from the group consisting of palbociclib (PALB), ribociclib, aminociclib, abemaciclib, trilaciclib, voruciclib, purvalanol A and olomoucine II.
While Nencioni does not teach a CDK4/6 inhibitor, one of ordinary skill in the art would have a reasonable expectation of success to select a CDK4/6 inhibitor such as palbociclib, ribociclib, or abemaciclib because these CDK4/6 inhibitors are commonly known in the art for the treatment of BC in combination with antiestrogenic agents.
For example, see Portman, Table 2, p. R19 cited above.
Therefore, claim 22 was prima facie obvious at the time of filing.
Claim 23 is directed towards the method of claim 17, wherein said reduced calorie intake is a daily calorie intake reduced by 10-100% with respect to the normal daily calorie intake, which is 2000-3000 kcal/day for an adult male subject and 1600-2400 kcal/day for an adult female subject. Claim 24 is directed towards the method of claim 23, wherein said reduced calorie intake is a daily calorie intake reduced by 50-100% with respect to said normal daily calorie intake. Claim 25 is directed towards the method of claim 23, wherein said reduced calorie intake is a daily calorie intake reduced by 75- 100% with respect to said normal daily calorie intake.
One of ordinary skill in the art would have a reasonable expectation of success to reduce the calorie intake by 10-100%, 50-100% or 75-100% with respect to the regular calorie intake because Nencioni teaches “By reduced caloric intake it is hereby meant a daily caloric intake reduced by 10-100%, preferably by 50-100%, more preferably by 75-100%, with respect to the regular caloric intake,” (Nencioni, Specification, p. 4, lines 3-5). Nencioni teaches, “As a rough guide, subject's normal caloric intake is on average 2600 kcal/day for men and 1850 kcal/day for women.” (id., lines 9-10).
Therefore, claims 23-25 were prima facie obvious at the time of filing.
Claim 26 is directed towards the method of claim 23, wherein said reduced calorie intake is a daily calorie intake reduced by 10-85% with respect to said normal daily calorie intake and said patient is fed with foods with a high content of monounsaturated and polyunsaturated fats and a reduced content of proteins and carbohydrates (> 50% of the calories coming from said fats).
One of ordinary skill in the art would have a reasonable expectation of success to reduce calorie intake by 10-85% and feed the patient foods with a high content of monounsaturated and polyunsaturated fats and a reduced content of proteins and carbohydrates (>50% of the calories coming from said fats) because Nencioni teaches a similar diet:
Preferably, when the daily caloric intake is reduced by 10-85%, the patient is fed with foods with a high content of monounsaturated and polyunsaturated fats and a reduced content of proteins and sugars (≥ 40% of calories coming from fat).
Nencioni, Specification, p. 20-21, lines 11-14.
Greater than 40% overlaps the range of greater than 50% and therefore a prima facie case of obviousness exists (MPEP § 2144.05). Nencioni also claims that the food has ≥ 50% of calories coming from fat (Nencioni, p. 20-21, claim 8).
Therefore, claim 26 was prima facie obvious at the time of filing.
Claim 27 is directed towards the method of claim 23, wherein said period of reduced calorie intake is of 48 to 150 hours.
One of ordinary skill in the art would have a reasonable expectation of success to reduce calorie intake over a period of 48-150 hours because Nencioni teaches “Preferably said period of reduced caloric intake ranges from 48 to 150 hours, and most preferably it is of about 120 hours.” (Nencioni, Specification, lines 16-17).
Therefore, claim 27 was prima facie obvious at the time of filing.
Claim 28 is directed towards the method of claim 17, wherein said period of reduced calorie intake with concurrent administration of the compound having antiestrogenic activity and of the CDK4/6 inhibitor to the patient is repeated one or more times after respective periods of 5-60 days, during which said patient is given the compound having antiestrogenic activity and the CDK4/6 inhibitor while following a diet involving a normal calorie intake.
One of ordinary skill in the art would have a reasonable expectation of success to repeat the reduced calorie intake period one or more times after respective periods of 5-60 days, during which said patient is given the compound having antiestrogenic activity and the CDK4/6 inhibitor while following a diet involving a normal calorie intake because Nencioni teaches “The above-mentioned period of reduced caloric intake with concurrent administration of the compound having antiestrogenic activity to the patient can be repeated one or more times after respective periods of 5-60 days, during which the patient is given the antiestrogenic compound while following a diet involving a regular caloric intake.” (Nencioni, Specification, p. 5, lines 2-6).
Therefore, claim 28 was prima facie obvious at the time of filing.
Claim 29 is directed towards the method of claim 17, wherein said reduced calorie intake corresponds to less than 1,200 kcal/day. Claim 30 is directed towards the method of claim 17, wherein said reduced calorie intake corresponds to 300-1,100 Kcal/day.
One of ordinary skill in the art would have a reasonable expectation of success to use a reduced calorie intake of less than 1,200 kcal/day or 300-1,100 kcal/day because this range overlaps the reduced calorie intakes taught by Nencioni.
For example, Nencioni teaches: “The above-mentioned reduced calorie intake regimen preferably corresponds to less than 800 kcal/day, more preferably 400Kcal/day.” (Nencioni, Specification, p. 5, lines 7-8). Furthermore, Nencioni teaches that preferably caloric intake is reduced preferably by 50-100% with respect to regular calorie intake which is 2,600 kcal/day for men (Id., p. 4, lines 3-10), which corresponds to 1,300 kcal/day or less for men. Nencioni also teaches a reduction of 10-85% (Nencioni, Specification, p. 20-21, lines 11-14) which corresponds to 390-2,340 kcal/day for men and 277.5-1,665 kcal/day for women. These ranges overlap or lie inside the claimed ranges and therefore a prima facie case of obviousness exists (MPEP § 2144.05).
Therefore, claims 29-30 were prima facie obvious at the time of filing.
Claim 35 is directed towards the method according to claim 17, wherein said therapeutic combination is a pharmaceutical composition comprising a compound having antiestrogenic activity, a CDK4/6 inhibitor and a pharmaceutically acceptable carrier.
Nencioni teaches a pharmaceutical composition comprising a compound with antiestrogenic activity and a pharmaceutically acceptable carrier, which can further comprise an additional chemotherapeutic agent (Nencioni, specification, p. 5, lines 21-27).
While Nencioni does not teach the additional agent is a CDK4/6 inhibitor, one of ordinary skill in the art would have a reasonable expectation of success to include a CDK4/6 inhibitor in the composition instead of a traditional chemotherapeutic agent because it is commonly known in the art to combine antiestrogenic agents with CDK4/6 inhibitors. For example, see the teachings of Portman cited above.
Therefore, claim 35 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Nonstatutory 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(s) 17-19, 22-30 and 35 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,963,941 B2 (herein “the ‘941 patent”) in view of Nencioni et al. (WO 2017/140641 A1) (of record, IDS cite no. 1) and Portman et al. (Endocrine-Related Cancer, Vol. 26, Issue 1, p. R15-R30, Jan. 2019).
The ‘941 patent is the U.S. filing of Nencioni et al. (WO 2017/140641 A1). The rejection of claims 17-19, 22-30 and 35 as obvious over Nencioni in view of Portman is incorporated herein by reference.
Although the claims at issue are not identical, they are not patentably distinct because the ‘941 application claims:
A method of treating estrogen-responsive breast cancer (BC) in a human patient, which method comprises subjecting said patient to reduced caloric intake for a period of 24-190 hours while said patient is being treated with a compound having antiestrogenic activity, wherein said compound is a SERM and is selected among the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, ospemifene, arzoxifene and bazedoxifene.
‘941 patent, claim 1.
The instant application claims:
A method of treating breast cancer (BC) or other estrogen- responsive tumors in a human patient with a therapeutic combination of a compound having antiestrogenic activity and a CDK4/6 inhibitor, wherein the method comprises subjecting said patient to reduced calorie intake for a period of 24-190 hours while said patient is being treated with said therapeutic combination.
Instant claim 1.
While the ‘941 application does not claim that the method additionally includes administering a CDK4/6 inhibitor along with the compound having antiestrogenic activity, one of ordinary skill in the art would have a reasonable expectation of success to combine the compound having antiestrogenic activity with a CDK4/6 inhibitor because this combination is commonly used in breast cancer therapy. For example, see the teachings of Portman above, incorporated herein by reference.
A comparison of the instant claims with the claims of the ‘941 patent and the prior art is shown below:
Instant Claim
‘941 patent
Nencioni
Portman
17. A method of treating breast cancer (BC) or other estrogen- responsive tumors in a human patient with a therapeutic combination of a compound having antiestrogenic activity and a CDK4/6 inhibitor, wherein the method comprises subjecting said patient to reduced calorie intake for a period of 24-190 hours while said patient is being treated with said therapeutic combination.
1. A method of treating estrogen-responsive breast cancer (BC) in a human patient, which method comprises subjecting said patient to reduced caloric intake for a period of 24-190 hours while said patient is being treated with a compound having antiestrogenic activity, wherein said compound is a SERM and is selected among the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, ospemifene, arzoxifene and bazedoxifene.
Nencioni demonstrates that FMDs increase the efficacy of antiestrogenic therapies such as tamoxifen and reduces resistance to antiestrogenic therapies such as tamoxifen by inhibiting the PI3K and mTOR pathways.
Portman teaches that the combination of CDK4/6 inhibitors and endocrine therapy is the new standard of care in some countries, and have demonstrated benefits in human BC patients (Portman, Abstract).
Portman teaches that targeting growth factor signaling pathways, such as the PI3K-mTOR signaling pathway, can help to treat resistance to CDK4/6 inhibitors and to combination treatment with antiestrogenic therapy (Portman, R21-R24).
18. The method of claim 17, wherein said compound having antiestrogenic activity is selected among the group consisting of selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs) and aromatase inhibitors (Ais).
1. A method of treating estrogen-responsive breast cancer (BC) in a human patient, which method comprises subjecting said patient to reduced caloric intake for a period of 24-190 hours while said patient is being treated with a compound having antiestrogenic activity, wherein said compound is a SERM and is selected among the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, ospemifene, arzoxifene and bazedoxifene.
In an aspect thereof, the present invention relates to a compound having antiestrogenic activity for use in a method for the treatment of BC or other estrogen-responsive tumors and cancers in a human patient, wherein the method comprises subjecting said patient to reduced caloric intake for a period of 24-190 hours while said patient is being treated with said compound having antiestrogenic activity. The above-mentioned compound having antiestrogenic activity is preferably selected among the group consisting of SERMs, SERDs, and of
Als. (Nencioni, Specification, p. 4-5)
Portman teaches CDK4/6 inhibitors in combination with tamoxifen (SERM), letrozole (AI), and/or fulvestrant (SERD) (Portman, Table 2, p. R19).
19. The method of claim 18, wherein the compound having antiestrogenic activity is a SERM and is selected among the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, ospemifene, arzoxifene and bazedoxifene.
1. A method of treating estrogen-responsive breast cancer (BC) in a human patient, which method comprises subjecting said patient to reduced caloric intake for a period of 24-190 hours while said patient is being treated with a compound having antiestrogenic activity, wherein said compound is a SERM and is selected among the group consisting of tamoxifen, raloxifene, toremifene, lasofoxifene, ospemifene, arzoxifene and bazedoxifene.
Among the SERMs that can be used in the present invention, the following are mentioned: tamoxifen, raloxifene, toremifene, lasofoxifene, ospemifene, arzoxifene, bazedoxifene. (Specification, p. 4, lines 18-20).
Portman teaches CDK4/6 inhibitors in combination with tamoxifen (SERM), letrozole (AI), and/or fulvestrant (SERD) (Portman, Table 2, p. R19).
22. The method of claim 17, wherein said CDK4/6 inhibitor is selected from the group consisting of palbociclib (PALB), ribociclib, aminociclib, abemaciclib, trilaciclib, voruciclib, purvalanol A and olomoucine II.
While the ‘941 patent does not claim a CDK4/6 inhibitor, one of ordinary skill in the art would have a reasonable expectation of success to select a CDK4/6 inhibitor such as palbociclib, ribociclib, or abemaciclib because these CDK4/6 inhibitors are commonly known in the art for the treatment of BC in combination with antiestrogenic agents. For example, see Portman, Table 2, p. R19 cited above.
23. The method of claim 17, wherein said reduced calorie intake is a daily calorie intake reduced by 10-100% with respect to the normal daily calorie intake, which is 2000-3000 kcal/day for an adult male subject and 1600-2400 kcal/day for an adult female subject.
2. The method according to claim 1, wherein said reduced caloric intake is a daily caloric intake reduced by 10-100%.
“As a rough guide, subject's normal caloric intake is on average 2600 kcal/day for men and 1850 kcal/day for women.” (Nencioni, Specification, p. 4, lines 9-10).
24. The method of claim 23, wherein said reduced calorie intake is a daily calorie intake reduced by 50-100% with respect to said normal daily calorie intake.
3. The method according to claim 2, wherein said reduced caloric intake is a daily caloric intake reduced by 50-100%.
“As a rough guide, subject's normal caloric intake is on average 2600 kcal/day for men and 1850 kcal/day for women.” (Nencioni, Specification, p. 4, lines 9-10).
25. The method of claim 23, wherein said reduced calorie intake is a daily calorie intake reduced by 75- 100% with respect to said normal daily calorie intake.
4. The method according to claim 2, wherein said reduced caloric intake is a daily caloric intake reduced by 75-100%.
“As a rough guide, subject's normal caloric intake is on average 2600 kcal/day for men and 1850 kcal/day for women.” (Nencioni, Specification, p. 4, lines 9-10).
26. The method of claim 23, wherein said reduced calorie intake is a daily calorie intake reduced by 10-85% with respect to said normal daily calorie intake and said patient is fed with foods with a high content of monounsaturated and polyunsaturated fats and a reduced content of proteins and carbohydrates (> 50% of the calories coming from said fats).
5. The method according to claim 2, wherein said reduced caloric intake is a daily caloric intake reduced by 10-85% and said patient is fed with foods with a high content of monounsaturated and polyunsaturated fats and a reduced content of proteins and carbohydrates (≥50% of the calories coming from said fats).
27. The method of claim 23, wherein said period of reduced calorie intake is of 48 to 150 hours.
6. The method according to claim 2, wherein said period of reduced caloric intake is of 48 to 150 hours.
28. The method of claim 17, wherein said period of reduced calorie intake with concurrent administration of the compound having antiestrogenic activity and of the CDK4/6 inhibitor to the patient is repeated one or more times after respective periods of 5-60 days, during which said patient is given the compound having antiestrogenic activity and the CDK4/6 inhibitor while following a diet involving a normal calorie intake.
7. The method according to claim 1, wherein said period of reduced caloric intake with concurrent administration of the compound having antiestrogenic activity to the patient is repeated one or more times after respective periods of 5-60 days, during which said patient is given the compound having antiestrogenic activity while following a diet involving a regular caloric intake.
29. The method of claim 17, wherein said reduced calorie intake corresponds to less than 1,200 kcal/day.
8. The method according to claim 1, wherein said reduced caloric intake corresponds to less than 300 kcal/day.
2. The method according to claim 1, wherein said reduced caloric intake is a daily caloric intake reduced by 10-100%.
3. The method according to claim 2, wherein said reduced caloric intake is a daily caloric intake reduced by 50-100%.
“The above-mentioned reduced calorie intake regimen preferably corresponds to less than 800 kcal/day, more preferably 400Kcal/day.” (Nencioni, Specification, p. 5, lines 7-8). Furthermore, Nencioni teaches that preferably caloric intake is reduced preferably by 50-100% with respect to regular calorie intake which is 2,600 kcal/day for men (Id., p. 4, lines 3-10), which corresponds to 1,300 kcal/day or less for men. Nencioni also teaches a reduction of 10-85% (Nencioni, Specification, p. 20-21, lines 11-14) which corresponds to 390-2,340 kcal/day for men and 277.5-1,665 kcal/day for women.
30. The method of claim 17, wherein said reduced calorie intake corresponds to 300-1,100 Kcal/day.
2. The method according to claim 1, wherein said reduced caloric intake is a daily caloric intake reduced by 10-100%.
3. The method according to claim 2, wherein said reduced caloric intake is a daily caloric intake reduced by 50-100%.
“The above-mentioned reduced calorie intake regimen preferably corresponds to less than 800 kcal/day, more preferably 400Kcal/day.” (Nencioni, Specification, p. 5, lines 7-8). Furthermore, Nencioni teaches that preferably caloric intake is reduced preferably by 50-100% with respect to regular calorie intake which is 2,600 kcal/day for men (Id., p. 4, lines 3-10), which corresponds to 1,300 kcal/day or less for men. Nencioni also teaches a reduction of 10-85% (Nencioni, Specification, p. 20-21, lines 11-14) which corresponds to 390-2,340 kcal/day for men and 277.5-1,665 kcal/day for women.
35. The method according to claim 17, wherein said therapeutic combination is a pharmaceutical composition comprising a compound having antiestrogenic activity, a CDK4/6 inhibitor and a pharmaceutically acceptable carrier.
Nencioni teaches a pharmaceutical composition comprising a compound with antiestrogenic activity and a pharmaceutically acceptable carrier, which can further comprise an additional chemotherapeutic agent (Nencioni, specification, p. 5, lines 21-27).
One of ordinary skill in the art would have a reasonable expectation of success to include a CDK4/6 inhibitor in the composition instead of a traditional chemotherapeutic agent because it is commonly known in the art to combine antiestrogenic agents with CDK4/6 inhibitors. For example, see the teachings of Portman cited above.
Given the above teachings, the claims as a whole are obvious over the ‘941 patent in view of Nencioni and Portman, and are rejected on the ground of nonstatutory double patenting.
Conclusion
No claim is found to be allowable.
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/HEATHER DAHLIN/Examiner, Art Unit 1629