DETAILED ACTION
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 .
Preliminary Amendment
The preliminary amendment dated 11/06/2025 has been entered. Claims 1, 6-19, and 22-40 are pending.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The earliest possible effective filing date for the instant claims is October 09, 2019 based on the filing date of the PCT application PCT/CN2019/110112
Election/Restriction
Applicant’s election without traverse of Group II in the reply filed on 11/06/2025 is acknowledged.
Claims 1 and 40 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Applicant’s species election in the reply filed on 11/06/2025 is acknowledged. Applicant elected without traverse:
Cetuximab as the EGFR inhibitor, cobimetinib as the MEK inhibitor, and palbociclib as the CDK 4/6 inhibitor in one single composition
Simultaneous administration as the mode of administration
Weekly as the frequency of administration
Non-small cell lung cancer as the species of cancer and
KRAS G12C as the species of mutation
Claims 9-11, 13-19, 22-23, and 34-36 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 6-8, 12, 24-33, 37-39 are under examination.
Claim Rejections - 35 USC § 103
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.
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.
2. Claims 6-8, 12, 24-33 and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang (WO 2018/223022 A1, filing date June 01, 2018, priority date June 02, 2017, IDS 08/18/2022: Foreign patent documents 22 citation) in view of Young-Kwang (Molecular Carcinogenesis 49:353–362 (2010)) and Zhou (Cancer Letters 408 (2017) 130-137).
Zhang teaches compositions and methods for treating cancers, including epithelial tumors, which comprises a combination of at least two agents such as an epidermal growth factor receptor (EGFR) inhibitor, a mitogen-activated protein kinase (MEK) 1/2 inhibitor; and a cyclin dependent kinase (CDK) 4/6 inhibitor (abstract, Zhang’s claim 1) as required by instant claim 6. The EGFR inhibitors (a) can be cetuximab and/or Osimertinib (page 1, Brief Summary section, 2nd paragraph, Zhang’s claim 2). The MEK 1/2 inhibitor (b) can be trametinib and/or cobimetinib (page 1, Brief Summary section, 3rd paragraph Zhang’s claim 2) and the CDK 4/6 inhibitor (c) can be palbociclib and/or abemaciclib (page 1, Brief Summary section, 4th paragraph, Zhang’s claim 3) (instant claims 8 and 12). The method comprises administering to the subject (instant claim 6), the combination of (a) and (b) as separate compositions, or together as part of the same composition, the combination of (a) and (c) as separate compositions, or together as part of the same composition or the combination of (a), (b), and (c) as separate compositions, or together as part of the same composition (page 1, Brief Summary section, 5th paragraph, Zhang’s claim 7)), the administration as part of the same composition reads as simultaneous administration (instant claim 24). The subject includes a human subject (page 9, 2nd paragraph), (instant claim 38) and a therapeutically “effective amount" is the amount of an agent (e.g., antibody, small molecule) needed to elicit the desired biological response following administration (page 9, 6th paragraph), (instant claims 6 and 12). The methods and compositions taught by Zhang can be used in the treatment of any variety of cancers. Including malignant epithelial tumor or carcinoma (page 20 4th paragraph, Zhang’s claim 8) and the carcinomas can include lung cancer (small cell lung cancer or non-small cell lung cancer (NSCLCs)) and pancreatic cancer (page 20 5th paragraph, Zhang’s claim 11) as required in instant claims 27-30). Zhang’s claim 16 recites the method wherein the combination of (a), (b), and (c) reduces cancer cell growth by about or at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 2000% or more relative to (a), (b), and/or (c) alone and claim 17 recites that the combination of (a), (b), and (c) synergistically reduces cancer cell growth and/or synergistically increases cancer cell-killing relative to (a), (b), and/or (c) alone, as required by instant claim 32. Since the combination of (a), (b), and (c) synergistically reduces cancer cell growth, this cell growth reduction can be interpreted as a reduction in (mean) tumor volume, including a reduction of 20-90% (instant claim 33 and 39).
In addition, and regarding the interpretive “wherein” clause recited in instant claims 33 (“…, wherein the method reduces mean tumor volume by about 20-95%”) and 39 (“…, wherein the method reduces the tumor volume by at least about 85%), the clauses do not recite any additional active method steps, but simply states a characterization or conclusion of the results of those steps. Therefore, the “wherein” clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171, 26 USPQ2d 1018, 1023 (Fed Cir. 1993) (“A ‘whereby’ clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim.”). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) (“A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”).
Zhang does not teach the absence of a KRAS inhibitors (instant claim 7) or the presence of KRAs mutations (instant claims 6, 25-26, 31)
Young-Kwang teaches that dual inhibition of EGFR and MEK signaling shows a synergistic effect on KRAS mutant gastric cancer (abstract) and for the treatment of KRAS mutant lung cancers (page 354, first column third paragraph) (instant claim 6, 27-29). Young-Kwang does not disclose the addition of a KRAS inhibitor in their compositions. That is, their compositions do not comprise a KRAS inhibitor (entire article) as required in instant claim 7. Young-Kwang also teaches the combination therapy effects of a EGFR and MEK inhibitors in NSCLCs by studying cells lines H358 and H23 which have the G12C mutation (table 3), (instant claims 6, 25-26 and 31).
Zhou teaches that CDK4/6 inhibitor in combination with a MEK inhibitor inhibited the growth of NSCLC xenografts (abstract) and of KRAS-mutated A549 and H460 cells (page 133, second column, first paragraph and Figure 1) (instant claim 6, 27-30). Zhou does not disclose the addition of a KRAS inhibitor in their compositions. That is, their compositions do not comprise a KRAS inhibitor (entire article) as required in instant claim 7.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Zhang, with Young-Kwang and Zhou to develop a method of treating cancer (with a KRAS mutation, as taught by Young-Kwang and Zhou) comprising the administration of (a) an EGFR) inhibitor; (b) a MEK 1/2 inhibitor; and (c) CDK 4/6 inhibitor as taught by Zhang. It would further be obvious not to include KRAS inhibitors when treating (instant claim 7) since both Young-Kwang and Zhou do not include any KRAS inhibitors in their studies. One of ordinary skill would have been motivated to do so because all three, Zhang, Young-Kwang and Zhou, use different combinations of those inhibitors to treat NSCLC. There would be a reasonable expectation of success because these inhibitors are well characterized and their combinations have been shown to have positive results (even synergistic results according to Zhang) reducing cell cancer growth.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
3. Claims 6, 8, 12 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang in view of Young-Kwang, Zhou and NCT00103207 (Cetuximab in Treating Patients With Recurrent or Stage IIIB or Stage IV Lung Cancer. v.170 (submission date 12/03/2012 https://clinicaltrials.gov/study/NCT00103207)
Zhang, Young-Kwang and Zhou teachings have been discussed above and incorporated herein. Zhang, Young-Kwang and Zhou do not teach how cetuximab is administered (instant claim 37).
NCT00103207 teaches the use of cetuximab for recurrent or Stage IIIB or Stage IV lung cancer (title) as a weekly intravenous (IV) infusion (over 60 minutes) at 250 mg/m2 from week 2 onwards after an initial loading dose of 400 mg/m2 (over 120 minutes) on week 1 until disease progression or unacceptable toxicity. The infusion rate of cetuximab was 5 mL/min or less. Each cycle was 28 days in length (arms and intervention section). Instant claim 37 is drawn to cetuximab administered to the subject in a weekly dose of about 400 mg/m2 infused over 120 minutes with a maximum infusion rate of 10 mg/min, followed by weekly dose of 250 mg/m2 infused over 60 minutes with a maximum infusion rate of 10 mg/min.
It would have been obvious to one of ordinary skill in the art to combine the teachings of Zhang, Young-Kwang and Zhou with NCT00103207 to develop a method of treating cancer (with a KRAS mutation) comprising the administration of (a) an EGFR) inhibitor such as cetuximab; (b) a MEK 1/2 inhibitor; and (c) CDK 4/6 inhibitor with a method of administering cetuximab to the subject . It would further be obvious that many of the parameters taught by NCT00103207, such cetuximab doses (initial dose and following doses), frequency and duration of administration, infusion time and maximum infusion rate etc., are clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ. It would have been customary for an artisan of ordinary skill to determine the optimal situation needed to achieve the desired results. The principle of law states from MPEP 2144.05: "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages." (Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382); Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 2.
One of ordinary skill would have been motivated to do so because both Zhang and NCT00103207 treat patients having lung cancer with cetuximab. There would be a reasonable expectation of success because cetuximab is well characterized and has been extensively studied in non-small cell lung cancer.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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.
4. Claims 6, 8, 12, 27-30, and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 7, and 8 of issued patent No. US 12/076,399 B2 (reference patent (Case No. 16/617,229) in view of Prior (Cancer Res. 2012 May 15;72(10), 2457-67)
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US 12/076,399 B2 are drawn to the method of using the same composition (cetuximab, cobimetinib and palbociclib). US 12/076,399 B2 claims recite a method of treating cancer (genus) and the instant application claims recite a method of treating cancer that has a KRAS mutation (species). Prior teaches that KRAS is the most frequently mutated isoform in most cancers with the extreme example of pancreatic cancer where 90% of tumors harbored KRAS mutations (page 2 Ras mutation frequencies section 1st paragraph and table 1). Therefore, it would be obvious that the cancer treatments recited in the reference patent claims would include cancers with KRAS mutations. The reference patent claims make obvious the instant application claims.
5. Claims 6, 8, 24, 27-28 and 32-38 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 6, 10, 14, 17-18 and 23 of issued patent No. US 11/753476 B2 (reference patent (Case No. 17/045,982) in view of Lutterbuese (PNAS, July 13, 2010. Vol. 107, no. 28 12605–12610)
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of US 11/753476 B2 are drawn to the method of using the same composition (cetuximab, cobimetinib and palbociclib) as the instant application. US 11/753476 B2 claims recite a method of treating cancer that has a BRAF mutation and the instant application claims recite a method of treating cancer that has a KRAS mutation. Lutterbuese teaches antibodies specific for EGFR that can eliminate KRAS- and BRAF-mutated colorectal cancer cells (CRC) (title and abstract) and these antibodies are active against a wide range of CRC cells with diverse mutations in the EGFR pathway (page 12609 2nd column1st paragraph) (both KRAS and BRAF are part of the signaling pathway downstream of EGRF). This reads on antibodies targeting EGRF, such as cetuximab, can be effective (and thus can be used for treatment) against cancers with a KRAS mutation and/or cancers with a BRAF mutation. Therefore, it would be obvious that cancer treatments comprising cetuximab, as recited in the reference patent claims and the instant claims, would include cancers with KRAS mutations and cancers with BRAF mutations. The reference patent claims make obvious the instant application claims.
6. Claims 6-8, 12, 24-27, 32-33, and 37-39 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7, 19-21, 24-26 and 30-32 of reference application No. 17/766,726
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of 17/766,726 are drawn to the method of using the same composition (cetuximab, cobimetinib and palbociclib). 17/766,726 claims recite a method of treating colorectal cancer with a KRAS mutation (species) and the instant application claims recite a method of treating cancer that has a KRAS mutation (genus). Since the instant application claims would include a colorectal cancer, the reference application claims would anticipate the instant application claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
7. Claims 6, 8, 27-29 and 32-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 6, 8, 2, 25, 28 and 32-33 of reference application patent No. 18/357,945 in view of Lutterbuese (PNAS, July 13, 2010. Vol. 107, no. 28 12605–12610)
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of 18/357,945 are drawn to the method of using the same composition (cetuximab, cobimetinib and palbociclib) as the instant application. 18/357,945 claims recite a method of treating cancer that has a BRAF mutation and the instant application claims recite a method of treating cancer that has a KRAS mutation. Lutterbuese teaches antibodies specific for EGFR that can eliminate KRAS- and BRAF-mutated colorectal cancer cells (CRC) (title and abstract) and these antibodies are active against a wide range of CRC cells with diverse mutations in the EGFR pathway (page 12609 2nd column1st paragraph) (both KRAS and BRAF are part of the signaling pathway downstream of EGRF). This reads on antibodies targeting EGRF such as cetuximab can be effective (and thus can be used for treating) against cancers with a KRAS mutation and/or cancers with a BRAF mutation. Therefore, it would be obvious that the cancer treatments comprising cetuximab as recited in the reference application claims and the instant claims would include cancers with KRAS mutations and cancers with BRAF mutations. The reference application claims make obvious the instant application claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
8. Claims 6, 8,12, 27-30, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 7-8, 11 and 17 of pending application No. 18/779,583 in view of Prior (Cancer Res. 2012 May 15;72(10), 2457-67)
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of 18/779,583 are drawn to the method of using the same composition (cetuximab, cobimetinib and palbociclib). 18/779,583 claims recite a method of treating cancer (genus) and the instant application claims recite a method of treating cancer that has a KRAS mutation (species). Prior teaches that KRAS is the most frequently mutated isoform in most cancers with the extreme example of pancreatic cancer where 90% of tumors harbored KRAS mutations (page 2 Ras mutation frequencies section 1st paragraph and table 1). Therefore, it would be obvious that the cancer treatments recited in the reference application claims would also comprise cancers with KRAS mutations. The reference application claims make obvious the instant application claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/JANET L ANDRES/Supervisory Patent Examiner, Art Unit 1671