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 .
DETAILED ACTION
Request for Continued Examination
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 May 13th 2025 has been entered.
All claims are either identical to or patentably indistinct from claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Status of the Claims
Claims 31, 33, 39, and 41-46 are pending. Claims 31, 33, 39, 42, and 45 are examined on their merits.
Information Disclosure Statement
The Information Disclosure Statement filed on December 2nd 2025 is in compliance with the provisions of 37 CFR 1.97 and has been considered in full. A signed copy of references cited from the IDS is included with this Office Action.
35 USC § 103 Rejections for Claims 31, 33, 39, 42, and 45 Maintained
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 rejection of claims 31, 33-37, 39, 42, and 45 under 35 U.S.C. 103 as being unpatentable over Goetz (Goetz, et al., Journal of Clinical Oncology, Vol. 33, No. 15 Suppl., published online May 20, 2015) in view of Goldhirsch (Goldhirsch et al., Annals of Oncology, Volume 20, Issue 8, 2009, Pages 1319-1329) is maintained.
Applicant’s arguments in the response filed on December 2nd 2025 are acknowledged. Applicant argues that the claims are nonobvious because
The treatment goals, timescales between EBC and MBC differ.
Cancer biology between EBC and MBC differ and other drugs considered successful in the metastatic breast cancer setting have failed in the past in the early breast cancer setting.
Goldhirsch is limited to cytotoxic chemotherapy.
The results are unexpected.
Regarding argument 1, the distinct treatment goals, timescales, and biology between EBC and MBC are acknowledged. In particular, it is noted that:
Early Breast Cancer
Metastatic Breast Cancer
Treatment Goals
Focused on cancer eradication
Focused on cancer control (preserving quality of life)
Treatment Timescales
Survival measured in years
Survival measured in months
In each aspect, the metastatic form is defined as generally being more aggressive and more difficult to deal with. The argument that the treatment goal and timescales are different is merely an expression that the metastatic cancer is more difficult to treat.
Regarding argument 2, applicant argues that the cancer biology of the MBC may have evolved significantly from the biology of the EBC, and therefore it is not reasonable to expect that drugs approved for metastatic breast cancer will be successful for the treatment of early-stage breast cancer. As evidence, applicant describes therapies which have been successful in the metastatic setting but failed in the early-stage setting, including Bevacizumab, Palbociclib, Lapatinib, Everolimus, and Gemcitabine. However, the treatment pipeline indicated (i.e. metastatic breast cancer approval [Wingdings font/0xE0] early-stage breast cancer approval) has been demonstrated several times in the past. That is, while the cancer biology may differ between EBC and MBC, it is still reasonably expected that treatments in the MBC setting will still be useful in the EBC setting. For example, the following drugs initially demonstrated efficacy in the metastatic breast cancer setting then later showed success in the early-breast cancer setting:
Tamoxifen12
Anastrozole34
Trastuzumab56
Pertuzumab78
Neratinib910
It is not argued that success in this setting would have been absolutely predictable, but only that it would have been reasonably expected, especially considering the commonality of this particular treatment pipeline. See MPEP 2143.02:
“Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")).”
Regarding argument 3, applicant argues that the standards defined by Goldhirsch are only intended to cover “cytotoxic chemotherapies” and not “molecularly targeted cancer therapies such as small-molecule kinase inhibitors and monoclonal antibodies.” However, much of Goldhirsch’s discussion is regarding trastuzumab, a targeted HER2-directed monoclonal antibody. Furthermore, Goldhirsch specifically states:
“Low estrogen receptor, HER2 overexpression, and increased proliferation predict response to chemotherapy in general, rather than being agent specific.”
[Goldhirsch, pg. 1322, Table 1]
That is, Goldhirsch defines a patient population wherein chemotherapy in general would be considered useful, and not any particular agent.
Regarding argument 4, applicant’s claim of unexpected results, the arguments presented in the previous actions have addressed this. See the previous arguments below.
Arguments Presented in the Previous Action
Applicant’s amendment in the response filed on May 13th 2025 is acknowledged. Applicant has amended claim 31 with the additional limitation “wherein the patient is treated for 2 years or until evidence of disease recurrence or other discontinuation criteria are met, whichever occurs first.” Regarding this amendment, the claim specifies 3 possible endpoints for the treatment:
Two years.
Evidence of disease recurrence.
When other discontinuation criteria are met.
Applicant argues that these three endpoints are not disclosed in Goetz, nor Goldhirsch, and the claims are therefore allowable. Examiner disagrees.
Regarding endpoint 1, Examiner acknowledges that Goetz does not explicitly state an endpoint for discontinuation of the treatment, and only discloses the timeline of “Abemaciclib 150 mg or placebo will be given continuously PO every 12 hours until progression, along with anastrozole 1 mg or letrozole 2.5 mg once daily at the investigator’s discretion, and assessments will occur every 28 days.” However, one of ordinary skill in the art would reasonably perform such a treatment for 2 years, because endocrine therapies, and aromatase inhibitor therapies in particular are known be administered over a two-year period (see Goldhirsch, pg. 1322, Table 1, Endocrine Therapies). One of ordinary skill in the art would therefore have a reasonable expectation of success in performing applicant’s chemoendocrine therapy, determined to be used in cases where endocrine therapy will not suffice (see the below 103 rejections), for a two-year period.
Regarding endpoint 2, when evidence of disease recurrence is found, one of ordinary skill in the art would recognize that the treatment is not achieving the desired outcome, and would therefore discontinue the treatment.
Regarding endpoint 3, by definition, when “other discontinuation criteria are met,” one of ordinary skill in the art would discontinue treatment.
In each case, one of ordinary skill in the art would reasonably discontinue the treatment after the defined endpoint is met, and before one of the other endpoints are met, because the endpoint is defined as the moment when treatment will discontinue.
Applicant’s arguments are therefore found not persuasive and the rejection of claims 31, 33-37, 39, 42, and 45 under 35 U.S.C. 103 as being unpatentable over Goetz in view of Goldhirsch is maintained.
Arguments Presented in the Previous Action
Applicant’s arguments in the response filed on September 12th 2024 are acknowledged. Applicant argues that one of ordinary skill in the art would not have had a reasonable expectation of success in treating node-positive, early stage, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer in a patient using the claimed combination of abemaciclib and an endocrine therapy (i.e. applicant argues that the effectiveness of such a treatment would have been unexpected). As evidence for such results, applicant has attached the FDA label for the described treatment and quotes Gil-Gil (Gil-Gil et al., The Breast 58 (2021) 160-169) who describes the treatment as “remarkable.” While both pieces of literature are evidence that the combination of abemaciclib and an endocrine therapy is successful for the treatment of the described cancer, neither demonstrates that the success of the treatment is unexpected.
As evidence, applicant provides a curve demonstrating disease-free survival of patients receiving the abemaciclib—endocrine therapy combination, in comparison to endocrine therapy alone. However, as demonstrated in Goldhirsch (see below), the described patient population (patients with node-positive, early stage, HR+, HER- breast cancer) would be expected to be responsive to a combination chemoendocrine therapy, and NOT to an endocrine therapy alone (Goldhirsch, Table 3, see below).
Furthermore, Goetz and the instant application demonstrate identical treatments for very similar patient populations, as evidenced in a comparison of the patient populations of Goetz and the instant application.
Goetz Patient Population
Claimed Patient Population
Breast Cancer
Breast Cancer
HR+
HR+
HER2-
HER2-
Node Positive
Node Positive
Highly Proliferative
Highly Proliferative
Metastatic (cancer has moved beyond the lymph nodes)
Early Stage (cancer has not moved beyond the lymph nodes)
The populations share significant characteristics, with the primary difference being whether or not the cancer has moved past the lymph nodes. One of ordinary skill in the art would reasonably expect the cancer to be more difficult to treat after it has moved past the lymph nodes and spread to other parts of the body. Therefore, one of ordinary skill in the art would have had a reasonable expectation of success in treating early-stage, node positive, HR+, HER2- breast cancer with the combination of abemaciclib and an endocrine therapy.
35 USC § 103 Rejections for Claims 31, 33, 39, 42, and 45 Reiterated
Claims 31, 33-37, 39, 42, and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Goetz (Goetz, et al., Journal of Clinical Oncology, Vol. 33, No. 15 Suppl., published online May 20, 2015) in view of Goldhirsch (Goldhirsch et al., Annals of Oncology, Volume 20, Issue 8, 2009, Pages 1319-1329).
The claims address treatment of early-stage breast cancer that has begun to spread to the lymph nodes, in the case where the cancer is hormone receptor-positive (HR+) and human epidermal growth factor 2-negative (HER2-). The suggested treatment method involves a particular chemoendocrine therapy, a combination of:
Letrozole, an aromatase inhibitor, which causes a decrease in hormone production, helpful for treating hormone receptor-positive cancers, and
Abemaciclib, a CDK4 inhibitor that interrupts cell proliferation to slow cancer spread
Claims 31, 39, 42, and 45 are directed towards a method of adjuvant treatment of node-positive, early stage, HR+, HER2- breast cancer at high risk of recurrence via the administration of 2.5 mg letrozole once daily and 150 mg abemeciclib twice daily.
Goetz teaches a treatment for HR+, HER2- breast cancer comprising administration of 2.5 mg letrozole once daily in combination with 150 mg abemaciclib every 12 hours (twice daily) (Goetz, methods).
Goetz does not explicitly teach this treatment in a patient population wherein the breast cancer is early stage, node-positive. However, one of ordinary skill in the art would have had a reasonable expectation of success, before the effective filing date, in treating the node-positive, early stage, HR+, HER2- breast cancer with the combination of the letrozole endocrine therapy and the CDK4 inhibitor, abemaciclib in order to prevent the spread of the cancer past the lymph nodes, because chemoendocrine therapies similar to the one described are a known treatment for early stage node-positive, HR+, HER2- breast cancer. For example, see Goldhirsch:
Goldhirsch approaches early-stage breast cancer and presents many recommended treatments for different circumstances. Specifically on node-positive, estrogen receptor-positive (a form of HR+), HER2- breast cancer, Goldhirsch teaches treatment with chemoendocrine therapies (Goldhirsch, Table 3, pg. 1324). Goldhirsch additionally teaches the use of aromatase inhibitors, as a treatment for high-risk hormone receptor-positive patients (Goldhirsch, pg. 1325, adjuvant systemic therapies).
Considering that the genus of the patient population presented by Goetz (patients with HR+, HER2- breast cancer) encompasses the entirety of the patient population presented by Goldhirsch (patients with early-stage, node-positive, estrogen receptor-positive, HER2- breast cancer), one of ordinary skill in the art would have therefore had a reasonable expectation of success in combining the teachings of Goetz and Goldhirsch, using the chemoendocrine therapy presented by Goetz to treat the specific patient population presented by Goldhirsch. Claims 31, 39, 42, and 45 are therefore prima facie obvious.
Claim 33 is directed towards the method of claim 31 wherein the patient has a Ki67 index of at least 20%. Ki67 is a protein marker that can be representative of cell proliferation. The Ki-67 index is representative of the fraction of tumor cells actively proliferating. One of ordinary skill in the art would have a reasonable expectation of success in slowing or stopping the cancer cell proliferation using a CDK4 inhibitor, such as abemaciclib, which is intended to have exactly this effect. For this reason, and the reasons elaborated in the rejection for claim 31, claim 33 is prima facie obvious.
Supporting Evidence Provided in Advisory Action Dated September 12th 2024 Reiterated
Applicant’s argument in the response filed on August 12th 2024 is acknowledged. Applicant argues on the basis of unexpected results that the combination of Goetz (Goetz et al., Journal of Clinical Oncology, Vol. 33, No. 15 Suppl., 2015) and Goldhirsch (Goldhirsch et al., Annals of Oncology, Vol. 20, Issue 8, 2009, pg. 1319-1329) does not render the claims obvious. The combination of Goetz and Goldhirsch as they apply to the claims is described below:
claims
Goetz
Goldhirsch
Patient population
Early stage, HR+, HER2-
late stage, HR+, HER2-
Early stage, HR+, HER2- (chemo depends on the whether the patient is Grade 1, 2 or 3 as shown in Table 3)
Drug 1
abemaciclib
abemaciclib
Chemo in general depending on the situation
Drug 2
Endocrine therapy (e.g., letrozole)
letrozole
Endocrine for all early stage, HR+, HER2- breast cancer
Applicant’s unexpected results claim is Not substantiated. The patient populations of Applicant’s alleged unexpected results, and those in Goetz, is that the breast cancer meets the following 4 criteria:
HR+
HER2-
Highly proliferative
Node positive
Goetz teach the following:
PNG
media_image1.png
263
787
media_image1.png
Greyscale
Goldhirsch clearly teaches that adding chemo should be done based on certain criteria, two of which are highly proliferative and being node positive for HR+ HER2- early stage breast cancer:
PNG
media_image2.png
612
1371
media_image2.png
Greyscale
In the context of a node-positive, early stage (that is, before the cancer has spread beyond the lymph nodes), HR+, HER2- breast cancer population, one of ordinary skill in the art would therefore find a reasonable expectation of success in treating the cancer with a chemoendocrine therapy, and particularly a therapy that has demonstrated success in the late stage (metastatic stage) of the same cancer, i.e. the claimed combination therapy of abemaciclib and an endocrine therapy demonstrated by Goetz.
The 103 rejection of claims 31, 33, 39, 42, and 45 as being prima facie obvious over Goetz (Goetz et al., Journal of Clinical Oncology, Vol. 33, No. 15 Suppl., 2015) in view of Goldhirsch (Goldhirsch et al., Annals of Oncology, Vol. 20, Issue 8, 2009, pg. 1319-1329) is thus maintained.
Nonstatutory Double Patenting Rejections Maintained
Applicant has requested that the nonstatutory double patenting rejection over copending Application No. 19/203,562 be held in abeyance. The rejection is thus maintained.
Nonstatutory Double Patenting Rejection Reiterated
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.
Claims 31, 33, 39, 42, and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 19/203,562 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application teaches administration of the same treatment to a patient population who has had a “prior diagnosis of” the same condition. As patients known to have the condition have necessarily received a diagnosis of the condition prior to the date of treatment, the two methods overlap in patient populations.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
All claims are either identical to or patentably indistinct from claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Anthony Seitz whose telephone number is (703)756-4657. The examiner can normally be reached 7:30 AM ET - 5:00 PM ET M-F.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571)272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/A.J.S./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 See Cole et al., A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer. 1971 Jun;25(2):270-5
2 See Fisher et al., Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001 May 2;93(9):684-90
3 See Nabholtz et al., Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000 Nov 15;18(22):3758-67
4 See Howell et al., ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005 Jan 1-7;365(9453):60-2.
5 See Slamon et al., Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92
6 See Romond et al., Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84
7 See Swain et al., CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015 Feb 19;372(8):724-34
8 See Gianni et al., 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800.
9 See Burstein et al., Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 2010 Mar 10;28(8):1301-7.
10 See Chan et al., ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-377