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
Claims 1-23 are pending.
Claim Interpretation
The instant application defines HER2-positive “early breast cancer” as breast cancer that has not spread beyond the breast or the axillary lymph nodes (instant specification, page 11, paragraph 33). This includes stage II and III breast cancers that have not progressed to stage IV (instant specification, page 11, paragraph 33).
Claim Objections Withdrawn
The previous rejection of claims 1-23 under 35 U.S.C. 102 is withdrawn in view of Hoffmann-La Roche et al. NCT01772472 Protocol for Trastuzumab Emtansine (https://cdn.clinicaltrials.gov/large-docs/72/NCT01772472/Prot_000.pdf reference of record) not being available for teaching administration of T-DM1 before the filing date of the instant application.
The previous rejection of claims 1-23 under nonstatutory double patenting is withdrawn in view of Hoffmann-La Roche et al. NCT01772472 Protocol for Trastuzumab Emtansine (https://cdn.clinicaltrials.gov/large-docs/72/NCT01772472/Prot_000.pdf reference of record) not being available for teaching administration of T-DM1 before the filing date of the instant application.
New Rejections
Claim Rejections – 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5-11, 13-18, and 20-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Krop et al. (Journal of Clinical Oncology, 2015 33(10:1136-1142 and supplemental protocol) “Krop and supp protocol” hereafter.
Regarding instant claims 1-3, 5-11, 13-18, and 20-23:
A) Krop and supp protocol taught a method of treating patients with HER2+ early-stage breast cancer by administering trastuzumab emtansine (T-DM1) (abstract), wherein the method comprises administering patients a pre-operative systemic treatment of neoadjuvant therapy of a chemotherapeutic followed by a HER2 targeting therapy of T-DM1, which comprises trastuzumab; performing surgery; optionally administering docetaxel and trastuzumab; and administering adjuvant T-DM1 as a monotherapy every three weeks (Supplemental page 27/P BO22857/TDM4874g-A1 and Supplemental Figure 1 Study Schema).
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B) Regarding residual disease, Krop and supp protocol taught the pCR (ypT0/is N0) rate was 56.0% (28 of 50 patients; 95% CI, 41.3% to 69.6%) in those who were administered neoadjuvant therapy (anthracycline followed by four T-DM1 cycles) and underwent surgery (page 1140, left column, Efficacy, first paragraph). Thus, the remaining 44% of patients following surgery had residual disease. Krop and supp protocol further taught pathologic complete response (pCR) rate for patients administered preoperative T-DM1, wherein pCR was defined as the absence of invasive neoplastic cells on microscopic examination of the original breast tumor area and axillary lymph nodes (ypT0/is, ypN0) after primary systemic therapy and surgery (page 1137, right column, Statistical Methods, first paragraph). Thus, early breast cancer patients following surgery that had residual disease were taught to be included in the treatment method.
C) Regarding the administration of T-DM1, Krop and supp protocol taught 3.6 mg/kg of T-DM1 was administered (Supplemental page 58/P BO22857/TDM4874g-A1, Administration and Dosage, first paragraph) and the first infusion of T-DM1 as administered over 90 minutes (±10 minutes) and subsequent infusions of T-DM1 as administered over 30 minutes (±10 minutes) (Supplemental page 59/P BO22857/TDM4874g-A1, first paragraph).
D) Regarding surgery, Krop and supp protocol taught at the completion of the neoadjuvant therapy, patients undergo surgery, wherein the desired outcome of the neoadjuvant therapy is pCR (Supplemental page 34/P BO22857/TDM4874g-A1, paragraph 2), wherein the tumor and lymph nodes are removed and examined for residual disease (Supplemental page 71/P BO22857/TDM4874g-A1, paragraph 1). Thus, the surgery is a definitive surgery.
Thus, Krop and supp protocol taught a method of adjuvant therapy in HER2+ early breast cancer patients following surgery that had residual disease, wherein the method comprised administering a pre-operative systemic treatment of neoadjuvant therapy of a chemotherapeutic followed by a HER2 targeting therapy of T-DM1, which comprises trastuzumab (instant claims 2-3 and 11); performing a definitive surgery, wherein the tumor and lymph nodes are removed and examined for residual disease; optionally administering docetaxel and trastuzumab or not (instant claims 14 and 18); and administering 3.6 mg/kg of adjuvant T-DM1 of every three weeks as a monotherapy (instant claim 5), wherein 3.6 mg/kg of T-DM1 is naturally a therapeutically effective amount as evidenced by the instant disclosure, wherein Figure 3 evidenced T-DM1 treated patients have better invasive disease-free survival, and wherein the first infusion of T-DM1 was administered over 90 minutes (±10 minutes) and subsequent infusions of T-DM1 were administered over 30 minutes (±10 minutes). This further meets the claim limitation of instant claims 1, 10, 13, 17.
Regarding instant claims 6-9, performing the method of Krop and supp protocol with T-DM1 above would naturally: increase IDFS (instant claim 6), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 7), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 8-9).
Regarding instant claims 15-16, performing the method of Krop and supp protocol with T-DM1 above will naturally: increase IDFS (instant claim 15) and decrease distant occurrence (instant claim 16).
Regarding instant claims 20-23, performing the method of Krop and supp protocol with T-DM1 above will naturally: increase IDFS (instant claim 20), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 22), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 21 and 23).
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.
Claims 1-23 are rejected under 35 U.S.C. 103 as being unpatentable over Krop et al (Journal of Clinical Oncology, 2015 33(10:1136-1142 and supplemental protocol) “Krop and supp protocol” hereafter and Bayraktar S et al. (J Clin Oncol 2009 27 15_suppl e11557).
Krop and supp protocol teach the limitations of claims 1-3, 5-11, 13-18, and 20-23 for the reasons set forth above.
Krop and supp protocol is described above.
Krop and supp protocol did not teach a neoadjuvant treatment comprising docetaxel (same as taxane) and trastuzumab, but this is obvious in view of Bayraktar
Bayraktar taught neoadjuvant chemotherapy for locally advanced breast cancer was shown to improve the complete pathologic (pCR) and clinical response (cCR) as well as the disease free survival (DFS), wherein a pre-operative systemic treatment comprising docetaxel and trastuzumab given every 3 weeks in HER2-positive breast cancer patients was effective, wherein patients had stage II HER2-positive breast cancer (abstract).
Regarding instant claims 4, 12, and 19, it would have been obvious for a person having ordinary skill in the art to take the method of Krop and supp above – and: exchange the neoadjuvant pre-operative systemic treatment comprising AC or FEC of Krop and supp for a neoadjuvant pre-operative systemic treatment comprising docetaxel and trastuzumab of Bayraktar.
This is obvious because: 1) Bayraktar taught administration of neoadjuvant chemotherapy comprising docetaxel and trastuzumab in patients with stage II HER2-positive breast cancer was shown to improve the complete pathologic (pCR) and clinical response (cCR) as well as the disease free survival (DFS). Stage II HER2-positive breast cancer is considered an early breast cancer.
There is a reasonable expectation of success because: 1) Bayraktar taught administration of neoadjuvant chemotherapy comprising docetaxel and trastuzumab in patients with stage II HER2-positive breast cancer was shown to improve the complete pathologic (pCR) and clinical response (cCR) as well as the disease free survival (DFS).
Claims 1-23 are rejected under 35 U.S.C. 103 as being unpatentable over Hoffmann-La Roche et al (KATHERINE) Clinical Trials NCT01772472 (https://classic.clinicaltrials.gov/ct2/history/NCT01772472?V_131=View#StudyPageTop Oct 12, 2017, reference of record) and Genentech KADCYLA® (ado-trastuzumab emtansine) prescribing information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125427s096lbl.pdf, 7/2016 reference of record).
Regarding instant claim 1, Hoffmann-La Roche taught a randomized, open-label study to evaluate the efficacy and safety of a method of treatment of trastuzumab emtansine (T-DM1) versus trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer who have residual tumor present in the breast or axillary lymph nodes following preoperative therapy, which is neoadjuvant therapy (instant claim 1) (page 9, Study Description, Brief Summary). Hoffmann-La Roche taught the method had surgical removal of all clinically evident disease in the breast and lymph nodes (page 11, Eligibility, Criteria, Inclusion Criteria, bullet 6). Hoffmann-La Roche taught the method treated patients with either trastuzumab emtansine at 3.6 mg/kg (instant claim 5) or trastuzumab at 6 mg/kg intravenously every 3 weeks for 14 cycles (page 9, Study Description, Brief Summary). Regarding the claim limitation of a therapeutically effective amount of T-DM1 as a monotherapy in instant claim 1, Hoffmann-La Roche taught the method treated patients with trastuzumab emtansine at 3.6 mg/kg (page 9, Study Description, Brief Summary) – this dose is necessarily therapeutic effective amount as evidenced by the instant disclosure, wherein Figure 3 evidenced T-DM1 treated patients have better invasive disease-free survival.
Regarding instant claims 2-5 and 10-13, Hoffmann-La Roche taught the performing the method in patients that completed preoperative systemic chemotherapy and HER2-directed treatment consisting of at least 6 cycles of chemotherapy with a total duration of at least 16 weeks, including at least 9 weeks of trastuzumab (instant claim 3), which is a HER2 targeted therapy (instant claim 2), and at least 9 weeks of taxane-based therapy (instant claim 4) (page 11, Eligibility, Criteria, Inclusion Criteria, bullet 5). Hoffmann-La Roche taught the method treated patients with either trastuzumab emtansine at 3.6 mg/kg (instant claim 5) or trastuzumab at 6 mg/kg intravenously every 3 weeks for 14 cycles (page 9, Study Description, Brief Summary). The method of Hoffman-La Roche above further contains the subject matter of instant claims 10-13, 17, and 19. Additionally, regarding the claim limitation of a therapeutically effective amount of T-DM1 as a monotherapy in instant claims 10, 13, and 17, Hoffmann-La Roche taught the method treated patients with trastuzumab emtansine at 3.6 mg/kg (page 9, Study Description, Brief Summary) – this dose is necessarily is a therapeutic effective amount as evidenced by the instant disclosure, wherein Figure 3 evidenced T-DM1 treated patients have better invasive disease-free survival. Regarding instant claim 14 and 18, the method does not comprise concurrent adjuvant treatment with chemotherapy.
Regarding instant claims 6-9, performing the method of Hoffmann-LaRoche with T-DM1 above will naturally: increase IDFS (instant claim 6), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 7), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 8-9). Regarding instant claims 15-16, performing the method of Hoffmann-LaRoche with T-DM1 above will naturally: increase IDFS (instant claim 15) and decrease distant occurrence (instant claim 16). Regarding instant claims 20-23, performing the method of Hoffmann-LaRoche with T-DM1 above will naturally: increase IDFS (instant claim 20), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 22), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 21 and 23).
Hoffmann-La Roche did not describe wherein the initial administration of T-DM1 occurs over about 80 minutes to about 100 minutes and subsequent administrations occur over about 20 minutes to about 40 minutes, but this is obvious in view of the known prescribed administration details of T-DM1 taught by Genentech.
Genentech taught KADCYLA® (ado-trastuzumab emtansine) prescribing information (page 1, paragraph 1). Genentech taught the recommended doses and schedules of ado-trastuzumab emtansine (T-DM1) as 3.6 mg/kg given as an intravenous infusion every 3 weeks, wherein the first infusion was administered over 90 minutes and subsequent infusions were administered over 30 minutes (page 3, 2.1 Recommended Doses and Schedules, paragraphs 1-4).
Regarding instant claims 1-23, it would have been obvious for a person having ordinary skill in the art to take the adjuvant early breast cancer treatment therapy method which naturally reduces the risk of cancer of Hoffmann-La Roche comprising:
a preoperative neoadjuvant therapy comprising a systemic chemotherapy of a taxane-based therapy (instant claim 4) and HER2-directed treatment of trastuzumab (instant claim 3), which is a HER2 targeted therapy (instant claim 2);
surgical removal of all clinically evident disease in the breast and lymph nodes; and
administering 3.6 mg/kg of T-DM1 every three weeks as an adjuvant monotherapy to early HER2-positive breast cancer patients who have residual tumor present in the breast or axillary lymph nodes, wherein 3.6 mg/kg is naturally a therapeutically effective amount,
– and: 1) administer the T-DM1 using the recommended administration protocol on the prescription information of T-DM1 comprising administering the first infusion over 90 minutes and subsequent infusions over 30 minutes as taught by Genentech.
This is obvious because: 1) the recommended prescription information of Genentech taught the recommended doses and schedules of ado-trastuzumab emtansine (T-DM1) as 3.6 mg/kg given as an intravenous infusion every 3 weeks, wherein the first infusion was administered over 90 minutes and subsequent infusions were administered over 30 minutes.
There is a reasonable expectation of success because: 1) the recommended prescription information of Genentech taught the recommended doses and schedules of ado-trastuzumab emtansine (T-DM1) as 3.6 mg/kg given as an intravenous infusion every 3 weeks, wherein the first infusion was administered over 90 minutes and subsequent infusions were administered over 30 minutes. Thus, the method of administration of T-DM1 overlaps with the FDA approved method of administration.
This would produce a method of adjuvant early breast cancer treatment therapy which naturally reduces the risk of cancer comprising:
a preoperative neoadjuvant therapy comprising a systemic chemotherapy of a taxane-based therapy (instant claim 4, 12, and 19) and HER2-directed treatment of trastuzumab (instant claims 3 and 11), which is a HER2 targeted therapy (instant claim 2);
surgical removal of all clinically evident disease in the breast and lymph nodes by definitive surgery; and
administering 3.6 mg/kg of T-DM1 every three weeks (instant claim 5) as an adjuvant monotherapy (instant claims 14 and 18) to early HER2-positive breast cancer patients who have residual tumor present in the breast or axillary lymph nodes, wherein the first infusion is administered over 90 minutes and subsequent infusions are over 30 minutes, wherein 3.6 mg/kg is naturally a therapeutically effective amount,
This further meets the claim limitation of instant claims 1, 10, 13, 17.
Regarding instant claims 6-9, performing the method of Hoffmann-La Roche and Genentech above would naturally: increase IDFS (instant claim 6), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 7), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 8-9).
Regarding instant claims 15-16, performing the method of Hoffmann-La Roche and Genentech above will naturally: increase IDFS (instant claim 15) and decrease distant occurrence (instant claim 16).
Regarding instant claims 20-23, performing the method of Hoffmann-La Roche and Genentech above will naturally: increase IDFS (instant claim 20), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 22), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 21 and 23).
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-23 are rejected under nonstatutory double patenting as being unpatentable over claims 1-19 of U.S. Patent No. US 11,406,715 (Guardino AE et al.) (Guardino ‘715) in view of Hoffmann-La Roche et al. (KATHERINE) Clinical Trials NCT01772472 (https://classic.clinicaltrials.gov/ct2/history/NCT01772472?V_131=View#StudyPageTop Oct 12, 2017, reference of record), Parker S et al. (Clinical guidelines for the management of breast cancer. West Midlands Clinical Networks and Clinical Senate, reference of record), and Genentech KADCYLA® (ado-trastuzumab emtansine) prescribing information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125427s096lbl.pdf, 7/2016 reference of record).
The instant application defines HER2-positive “early breast cancer” as breast cancer that has not spread beyond the breast or the axillary lymph nodes (instant specification, page 11, paragraph 33). This includes stage II and III breast cancers that have not progressed to stage IV (instant specification, page 11, paragraph 33). Guardino ‘715 describes a method of treatment for “locally advanced” breast cancer in patented claim 1, which the specification states is a Stage II and III cancer which exhibits involvement of the local lymph nodes (Guardino ‘715 specification, page 17-18, column 8 last paragraph and column 9 first paragraph). Thus, a patient with residual disease present in a breast and/or axillary lymph node is a locally advanced patient.
Thus, Guardino ‘715 taught a method of treating an early HER2-positive patient with residual disease present in a breast and/or axillary lymph node comprising administering a therapeutically effective amount of an anti-HER2-maytansinoid conjugate, wherein the patient received prior treatment of a taxane prior to progression to positive locally advanced or metastatic disease and the last prior dose of the taxane treatment was at least ≥6 months before administration of the anti-HER2-maytansinoid conjugate, and wherein after the patient's cancer progressed to HER2-positive locally advanced or metastatic disease but prior to treatment with the anti-HER2-maytansinoid conjugate, the patient has not been treated with any chemotherapy in patented claim 1. Guardino ‘715 taught the anti-HER2-maytansinoid conjugate is a trastuzumab-maytansinoid conjugate (patented claim 16), a trastuzumab-DM1 conjugate (patented claim 17), or trastuzumab-MCC-DM1, which is also known as T-DM1 (patented claim 18), wherein the T-DM1 is administered every three weeks at 3.6 mg/kg (patented claim 19) or every week at 2.4 mg/kg (patented claim 20). Guardino ‘715 further taught the prior treatment in the method as: comprising a taxane and a HER2-directed therapy (patented claim 2 and 4) or a taxane and trastuzumab (patented claim 3), wherein the prior treatment was administered in the adjuvant (patented claim 5) or neoadjuvant (patented claim 6) setting. Thus, surgery can be performed before or after the prior treatment. Guardino ‘715 taught further details of the prior treatment in the method: wherein the taxane administered is paclitaxel (patented claim 7-9) or docetaxel (patented claim 10-12); wherein the trastuzumab (copending claims 13-14) or pertuzumab (copending claim 15) is administered at specific regimens.
Guardino ‘715 did not recite performing surgery after the prior treatment of the taxane and trastuzumab and before the T-DM1 in the adjuvant setting or wherein the initial administration of T-DM1 occurs over about 80 minutes to about 100 minutes and subsequent administrations occur over about 20 minutes to about 40 minutes, but this is addressed by Hoffmann-La Roche, Parker, and Genentech.
Hoffmann-La Roche is described above.
Parker taught that surgery remains the mainstay of early breast cancer treatment (page 16, second to last paragraph).
Genentech taught KADCYLA® (ado-trastuzumab emtansine) prescribing information (page 1, paragraph 1). Genentech taught the recommended doses and schedules of ado-trastuzumab emtansine (T-DM1) as 3.6 mg/kg given as an intravenous infusion every 3 weeks, wherein the first infusion was administered over 90 minutes and subsequent infusions were administered over 30 minutes (page 3, 2.1 Recommended Doses and Schedules, paragraphs 1-4).
Regarding claims 1-5, 10-14, and 17-19, it would have been obvious for a person having ordinary skill in the art to perform the patented method of Guardino ‘715 of treating an early HER2-positive patient with residual disease present in a breast and/or axillary lymph node, which is an early breast cancer, comprising administering a therapeutically effective amount of the anti-HER2-maytansinoid conjugate, trastuzumab-MCC-DM1, which is also known as T-DM1 (patented claim 18), wherein the T-DM1 is administered every three weeks at 3.6 mg/kg (patented claim 19), which would be T-DM1 monotherapy, wherein the patient received prior treatment comprising a taxane and a HER2-directed therapy (patented claim 2 and 4) or a taxane and trastuzumab (patented claim 3), wherein the prior treatment was administered in the neoadjuvant setting (patented claim 6) before administration of the anti-HER2-maytansinoid conjugate (patented claim 1) – and: 1) to further perform surgery after the prior neoadjuvant treatment after the HER2 breast cancer became invasive as taught by Hoffmann-La Roche; and 2) administer the initial T-DM1 dose over 90 minutes and administer subsequent infusions over 30 minutes as taught by Genentech.
This is obvious because: 1) Hoffmann-La Roche taught the method of treatment of patients with HER2+ early breast cancer previously treated with a taxane and trastuzumab as neoadjuvant therapy, then surgery to remove all traces of cancer followed by adjuvant T-DM1; and 2) the recommended prescription information of Genentech taught the recommended doses and schedules of ado-trastuzumab emtansine (T-DM1) as 3.6 mg/kg given as an intravenous infusion every 3 weeks, wherein the first infusion was administered over 90 minutes and subsequent infusions were administered over 30 minutes.
There is a reasonable expectation of success because: 1) Parker taught that surgery remains the mainstay of early breast cancer treatment. Further, removal of any residual HER2+ breast cancer following neoadjuvant treatment would decrease the number of cancer cells that the T-DM1 would need to kill; and 2) this dosage schedule is the recommended prescription dose and schedule of T-DM1 as taught by Genentech.
This would produce a method of treating a HER2-positive early breast cancer patient with residual disease present in a breast and/or axillary lymph node comprising administering a therapeutically effective amount of T-DM1 (patented claim 18), wherein the T-DM1 is administered every three weeks at 3.6 mg/kg (instant claim 5), which would be T-DM1 monotherapy, wherein the administration of the initial dose of T-DM1 is performed over 90 minutes and administration of subsequent infusions are performed over 30 minutes, wherein the patient received prior treatment comprising a taxane and trastuzumab (instant claims 2-4), wherein the prior treatment was administered in the neoadjuvant setting (patented claim 6), followed by surgery to remove all residual breast cancer before administration of the T-DM1 (instant claim 1). The method of Guardino ‘715, Hoffmann-La Roche, and Parker above further contains the subject matter of instant claims 10-13, 17, and 19. Regarding instant claim 14 and 18, the method does not comprise concurrent adjuvant treatment with chemotherapy.
Regarding instant claims 6-9, the method of Guardino ‘715, Hoffmann-La Roche, Parker, and Genentech above would naturally: increase IDFS (instant claim 6), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 7), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 8-9). Regarding instant claims 15-16, the method of Guardino ‘715, Hoffmann-La Roche, Parker, and Genentech above would naturally: increase IDFS (instant claim 15) and decrease distant occurrence (instant claim 16). Regarding instant claims 20-23, the method of Guardino ‘715, Hoffmann-La Roche, Parker, and Genentech above would naturally: increase IDFS (instant claim 20), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 22), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 21 and 23).
Response to Arguments
Applicant argues similar to the novelty rejection discussed above, the Office asserts that a skilled artisan would be able to arrive at the claimed invention by performing the method of the '715 patent and the '466 application in view of the KATHERINE Study Page, as evidenced by the disclosures provided by the KATHERINE Protocol. Because the '715 patent and the '466 application are
silent on infusion duration recited in claims 1, 10, 13, and 17, the Office again attempts to rely on the teachings the KATHERINE Protocol to supplement the disclosure of the Kadcyla Study Page such that one of skill in the art would allegedly perform the methods of the '715 patent and the '466 application with the claimed infusion durations (see the Office Action at page 13, 19, and 25). As discussed in detail above, the KATHERINE Protocol is not only a post-filing reference, but it is improper to use such a reference to supplement the disclosure of the KATHERINE Study Page as suggested by the Office.
In response, Applicant’s arguments, see page 7, paragraph 2, filed 10/27/2025, with respect to the rejection(s) of claim(s) 1-23 under nonstatutory double patenting have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of claims 1-19 of U.S. Patent No. US 11,406,715 (Guardino AE et al.) (Guardino 715) in view of Hoffmann-La Roche et al. (KATHERINE) Clinical Trials NCT01772472 (https://classic.clinicaltrials.gov/ct2/history/NCT01772472?V_131=View#StudyPageTop Oct 12, 2017, reference of record), Parker S et al. (Clinical guidelines for the management of breast cancer. West Midlands Clinical Networks and Clinical Senate, reference of record), and Genentech KADCYLA® (ado-trastuzumab emtansine) prescribing information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125427s096lbl.pdf, 7/2016 reference of record), wherein Hoffmann-La Roche et al. NCT01772472 Protocol for Trastuzumab Emtansine (https://cdn.clinicaltrials.gov/large-docs/72/NCT01772472/Prot_000.pdf reference of record) is not used. The rejection is above.
Applicant argues The Office also relies on the KADCYLA Label as teaching the recommended dosing schedule for T-DM1, however the KADCYLA Label cannot remedy the deficiencies in the KATHERINE Study Page because the KADCYLA Label does not disclose the claimed patient population. Moreover, the Office argues Parker renders claims 10-13, 17 and 19 as obvious because the cited reference teaches surgery remains the mainstay of early breast cancer treatment. Parker, however, is completely silent on as to infusion durations for administering T-DM1, as recited in the pending claims. As such, the KATHERINE Study Page, Parker, and the KADCYLA
Label, in any combination, fail to cure the deficiencies of the '715 patent and the '466 application, particularly given that the KATHERINE Protocol cannot be used to supplement their teachings as alleged by the Office and therefore the cited art does not provide the requisite guidance for a skilled artisan to arrive at the method as claimed.
Applicant's arguments filed 10/27/2025 have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the updated rejection above:
Guardino ‘715 provides the patient population for treating a HER2-positive patient with residual disease present in a breast and/or axillary lymph node, which is an early breast cancer, comprising administering a therapeutically effective amount of the anti-HER2-maytansinoid conjugate, trastuzumab-MCC-DM1, which is also known as T-DM1 (patented claim 18), wherein the T-DM1 is administered every three weeks at 3.6 mg/kg (patented claim 19), which would be T-DM1 monotherapy, wherein the patient received prior treatment comprising a taxane and a HER2-directed therapy (patented claim 2 and 4) or a taxane and trastuzumab (patented claim 3), wherein the prior treatment was administered in the neoadjuvant setting (patented claim 6) before administration of the anti-HER2-maytansinoid conjugate (patented claim 1);
Performing surgery after the prior neoadjuvant treatment after the HER2 breast cancer became invasive was taught by Hoffmann-La Roche; and
The timing of administration of the initial T-DM1 dose of over 90 minutes and administration of subsequent infusions of T-DM1 over 30 minutes was taught by the prescription information of Genentech.
The obvious rational is above.
Claims 1-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. US 17/813466 (Guardino AE et al.)(Guardino ‘466) in view of Hoffmann-La Roche et al. (KATHERINE) Clinical Trials NCT01772472 (https://classic.clinicaltrials.gov/ct2/history/NCT01772472?V_131=View#StudyPageTop Oct 12, 2017, reference of record), Parker S et al. (Clinical guidelines for the management of breast cancer. West Midlands Clinical Networks and Clinical Senate, reference of record), and Genentech KADCYLA® (ado-trastuzumab emtansine) prescribing information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125427s096lbl.pdf, 7/2016 reference of record).
The instant application defines HER2-positive “early breast cancer” is used to refer to breast cancer that has not spread beyond the breast or the axillary lymph nodes (specification, page 11, paragraph 33). This includes stage II and III breast cancers that have not progressed to stage IV (specification, page 11, paragraph 33). Guardino ‘466 describes a method of treatment for “locally advanced” breast cancer in copending claim 1, which the specification states is a Stage II and III cancer which exhibits involvement of the local lymph nodes (specification, page 17-18, column 8 last paragraph and column 9 first paragraph). Thus, a patient with residual disease present in a breast and/or axillary lymph node is a locally advanced patient.
Thus, Guardino ‘466 taught a method of treating an early HER2-positive patient with residual disease present in a breast and/or axillary lymph node comprising administering a therapeutically effective amount of an anti-HER2-maytansinoid conjugate, wherein the patient received prior treatment of a taxane prior to progression to positive locally advanced or metastatic disease and the last prior dose of the taxane treatment was at least ≥6 months before administration of the anti-HER2-maytansinoid conjugate, and wherein after the patient's cancer progressed to HER2-positive locally advanced disease but prior to treatment with the anti-HER2-maytansinoid conjugate, the patient has not been treated with any chemotherapy in copending claim 1. Guardino ‘466 taught the anti-HER2-maytansinoid conjugate is a trastuzumab-maytansinoid conjugate (copending claim 16), a trastuzumab-DM1 conjugate (copending claim 17), or trastuzumab-MCC-DM1, which is also known as T-DM1 (copending claim 18), wherein the T-DM1 is administered every three weeks at 3.6 mg/kg (copending claim 19) or every week at 2.4 mg/kg (copending claim 20). Guardino ‘466 further taught the prior treatment in the method as: comprising a taxane and a HER2-directed therapy (copending claim 2) or a taxane and trastuzumab (copending claims 3-4), wherein the prior treatment was administered in the adjuvant (copending claim 5) or neoadjuvant (copending claim 6) setting. Thus, surgery can be performed before or after the prior treatment. Guardino ‘466 taught further details of the prior treatment in the method: wherein the taxane administered is paclitaxel (copending claim 7-9) or docetaxel (copending claim 10-12); wherein the trastuzumab (copending claims 13-14) or pertuzumab (copending claim 15) is administered at specific regimens.
Guardino ‘466 did not recite performing surgery after the prior treatment of the taxane and trastuzumab and before the T-DM1 in the adjuvant setting or wherein the initial administration of T-DM1 occurs over about 80 minutes to about 100 minutes and subsequent administrations occur over about 20 minutes to about 40 minutes, but this is addressed by Hoffmann-La Roche, Parker, and Genentech.
Hoffmann-La Roche, Parker, and Genentech are described above.
Regarding claims 1-5, 10-14, and 17-19, it would have been obvious for a person having ordinary skill in the art to perform the copending method of Guardino ‘466 of treating a HER2-positive patient with residual disease present in a breast and/or axillary lymph node comprising administering a therapeutically effective amount of the anti-HER2-maytansinoid conjugate, trastuzumab-MCC-DM1, which is also known as T-DM1 (copending claim 18), wherein the T-DM1 is administered every three weeks at 3.6 mg/kg (copending claim 19), which would be T-DM1 monotherapy, wherein the patient received prior treatment comprising a taxane and a HER2-directed therapy (copending claims 2 and 4) or a taxane and trastuzumab (copending claim 3), wherein the prior treatment was administered in the neoadjuvant setting (copending claim 6) before administration of the anti-HER2-maytansinoid conjugate (copending claim 1) – and: 1) to further perform surgery after the prior neoadjuvant treatment after the HER2 breast cancer became invasive as taught by Hoffmann-La Roche; and 2) administer the initial T-DM1 dose over 90 minutes and administer subsequent infusions over 30 minutes as taught by Genentech.
This is obvious because: 1) Hoffmann-La Roche taught the method of treatment of patients with HER2+ early breast cancer previously treated with a taxane and trastuzumab as neoadjuvant therapy, then surgery to remove all traces of cancer followed by adjuvant T-DM1; and 2) the recommended prescription information of Genentech taught the recommended doses and schedules of ado-trastuzumab emtansine (T-DM1) as 3.6 mg/kg given as an intravenous infusion every 3 weeks, wherein the first infusion was administered over 90 minutes and subsequent infusions were administered over 30 minutes.
There is a reasonable expectation of success because: 1) Parker taught that surgery remains the mainstay of early breast cancer treatment. Further, removal of any residual HER2+ breast cancer following neoadjuvant treatment would decrease the number of cancer cells that the T-DM1 would need to kill; and 2) this dosage schedule is the recommended prescription dose and schedule of T-DM1 as taught by Genentech.
This would produce a method of treating an early HER2-positive patient with residual disease present in a breast and/or axillary lymph node comprising administering a therapeutically effective amount of T-DM1 (patented claim 18), wherein the T-DM1 is administered every three weeks at 3.6 mg/kg (instant claim 5), which would be T-DM1 monotherapy, wherein the administration of the initial dose of T-DM1 is performed over 90 minutes and administration of subsequent infusions are performed over 30 minutes, wherein the patient received prior treatment comprising a taxane and trastuzumab (instant claims 2-4), wherein the prior treatment was administered in the neoadjuvant setting (patented claim 6), followed by surgery to remove all residual breast cancer before administration of the T-DM1 (instant claim 1). The method of Guardino ‘466, Hoffmann-La Roche, Parker, and Genentech above further contains the subject matter of instant claims 10-13, 17, and 19. Regarding instant claim 14 and 18, the method does not comprise concurrent adjuvant treatment with chemotherapy.
Regarding instant claims 6-9, the method of Guardino ‘466, Hoffmann-La Roche, Parker, and Genentech above would naturally: increase IDFS (instant claim 6), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 7), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 8-9). Regarding instant claims 15-16, the method of Guardino 466, Hoffmann-La Roche, Parker, and Genentech above would naturally: increase IDFS (instant claim 15) and decrease distant occurrence (instant claim 16). Regarding instant claims 20-23, the method of Guardino ‘466, Hoffmann-La Roche, Parker, and Genentech above would naturally: increase IDFS (instant claim 20), provide a 50% reduction in the risk of invasive disease recurrence as compared to adjuvant therapy with trastuzumab (instant claim 22), and provide a 40% reduction in the risk of distant recurrence as compared to adjuvant therapy with trastuzumab (instant claim 21 and 23).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Arguments
The response to the arguments of the '715 patent and the '466 application are above.
Applicant argues The Office also relies on the KADCYLA Label as teaching the recommended dosing schedule for T-DM1, however the KADCYLA Label cannot remedy the deficiencies in the KATHERINE Study Page because the KADCYLA Label does not disclose the claimed patient population. Moreover, the Office argues Parker renders claims 10-13, 17 and 19 as obvious because the cited reference teaches surgery remains the mainstay of early breast cancer treatment. Parker, however, is completely silent on as to infusion durations for administering T-DM1, as recited in the pending claims. As such, the KATHERINE Study Page, Parker, and the KADCYLA
Label, in any combination, fail to cure the deficiencies of the '715 patent and the '466 application, particularly given that the KATHERINE Protocol cannot be used to supplement their teachings as alleged by the Office and therefore the cited art does not provide the requisite guidance for a skilled artisan to arrive at the method as claimed.
In response, Applicant's arguments filed 10/27/2025 have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the updated rejection above:
the copending method of Guardino ‘466 provides the patient population for treating a HER2-positive patient with residual disease present in a breast and/or axillary lymph node comprising administering a therapeutically effective amount of the anti-HER2-maytansinoid conjugate, trastuzumab-MCC-DM1, which is also known as T-DM1 (copending claim 18), wherein the T-DM1 is administered every three weeks at 3.6 mg/kg (copending claim 19), which would be T-DM1 monotherapy, wherein the patient received prior treatment comprising a taxane and a HER2-directed therapy (copending claims 2 and 4) or a taxane and trastuzumab (copending claim 3), wherein the prior treatment was administered in the neoadjuvant setting (copending claim 6) before administration of the anti-HER2-maytansinoid conjugate (copending claim 1) – and: 1) to further perform surgery after the prior neoadjuvant treatment after the HER2 breast cancer became invasive as taught by Hoffmann-La Roche;
Performing surgery after the prior neoadjuvant treatment after the HER2 breast cancer became invasive was taught by Hoffmann-La Roche; and
The timing of administration of the initial T-DM1 dose of over 90 minutes and administration of subsequent infusions of T-DM1 over 30 minutes was taught by the prescription information of Genentech.
The obvious rational is above.
Claims 1-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-19 of copending Application No. US 19/288,035 (Guardino AE et al.)(Guardino ‘035) in view of Hoffmann-La Roche et al. (KATHERINE) Clinical Trials NCT01772472 (https://classic.clinicaltrials.gov/ct2/history/NCT01772472?V_131=View#StudyPageTop Oct 12, 2017, reference of record), Parker S et al. (Clinical guidelines for the management of breast cancer. West Midlands Clinical Networks and Clinical Senate, reference of record), and Genentech KADCYLA® (ado-trastuzumab emtansine) prescribing information (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125427s096lbl.pdf, 7/2016 reference of record).
The instant application defines HER2-positive “early breast cancer” is used to refer to breast cancer that has not spread beyond the breast or the axillary lymph nodes (specification, page 11, paragraph 33). This includes stage II and III breast cancers that have not progressed to stage IV (specification, page 11, paragraph 33). Guardino ‘035 describes a method of treatment for “locally advanced” breast cancer in copending claim 1, which the specification states is a Stage II and III cancer which exhibits involvement of the local lymph nodes (specification, page 17-18, column 8 last paragraph and column 9 first paragraph). Thus, a patient with residual disease present in a breast and/or axillary lymph node is a locally advanced patient.
Thus, Guardino ‘035 taught a method of treating an early HER2-positive patient with residual disease present in a breast and/or axillary lymph node comprising administering a therapeutically effective amount of an anti-HER2-maytansinoid conjugate, wherein the patient received prior treatment of a taxane prior to progression to positive locally advanced or metastatic disease and the last prior dose of the taxane treatment was at least ≥6 months before administration of the anti-HER2-maytansinoid conjugate, and wherein after the patient's cancer progressed to HER2-positive locally advanced disease but prior to treatment with the anti-HER2-maytansinoid conjugate, the patient has not been treated with any chemotherapy in copending claim 1. Guardino ‘035 taught the anti-HER2-maytansinoid conjugate is a trastuzumab-maytansinoid conjugate (copending claim 16), a trastuzumab-DM1 conjugate (copending claim 17), or trastuzumab-MCC-DM1, which is also known as T-DM1 (copending claim 18), wherein the T-DM1 is administered every three weeks at 3.6 mg/kg (copending claim 19) or every week at 2.4 mg/kg (copending claim 20). Guardino ‘035 further taught the prior treatment in the method as: comprising a taxane and a HER2-directed therapy (copending claim 2) or a taxane and trastuzumab (copending claims 3-4), wherein the prior treatment was administered in the adjuvant (copending claim 5) or neoadjuvant (copending claim 6) setting. Thus, surgery can be performed before or after the prior treatment. Guardino ‘035 taught further details of the prior treatment in the method: wherein the taxane administered is paclitaxel (copending claim 7-9) or docetaxel (copending claim 10-12); wherein the trastuzumab (copending claims 13-14) or pertuzumab (copending claim 15) is administered at specific regimens.
Guardino ‘035 did not recite performing surgery after the prior treatment of the taxane and trastuzumab and before the T-DM1 in the adjuvant setting or wherein the initial administration of T-DM1 occurs over about 80 minutes to about 100 minutes and subsequent administrations occur over about 20 minutes to about 40 minutes, but this is addressed by Hoffmann-La Roche, Parker, and Genentech.
Hoffmann-La Roche, Parker, and Genentech are described above.
Regarding claims 1-5, 10-14, and 17-19, it would have been obvious for a person having ordinary skill in the art to perform the copending method of Guardino ‘035 of treating a HER2-po