DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 December 17, 2025 has been entered.
3. Claims 1, 17-21, 32-36, 40, 44-49, 51-54 and 68-74 are pending.
Claims 1, 17-21, 32-36, 40, 44-49, 51-54 and 68-74 are examined on the merits.
Maintained Grounds of Rejection
Claim Rejections - 35 USC § 103
4. 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 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.
5. 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.
6. The rejection of claims 1, 17-21, 32-36, 40, 44-49, 51-54 and 68-74 under 35 U.S.C. 103 as being unpatentable over Buchler et al. (BioMed Central Cancer 14 (323): 1-7, published May 7, 2014/ IDS reference CZ on sheet 5 submitted March 6, 2023), and further in view of ClinicalTrials.gov Identifier NCT02244632 (9 pages, publicly available September 19, 2014) and Spectrum Pharmaceuticals, Inc. (Fluorouracil injection, 8 pages, posted July 2016/ IDS reference CAA on sheet 5 submitted March 6, 2023) is maintained.
Applicant asserts “[t]he Office has cited the ClinicalTrials.gov Identifier NCT02244632 update posted on September 8, 2020 (Office Action at page 3, Notice of References Cited, and citation on Patent Center dated November 27, 2024) "publicly available" as of September 19, 2014 rather than the actual posting date of September 8, 2020. As discussed during the Examiner interview, and depicted in the Record History of ClinicalTrials.gov Identifier NCT02244632 (made of record in an IDS submitted herewith), the last publicly available entry prior to January 5, 2017 (one year prior to the effective filing date of the instant application) is August 30, 2016... As such, Applicant submits that the most current ClinicalTrials.gov Identifier NCT02244632 that could possibly be relied on as prior art is the August 30, 2016 entry.”, see Remarks submitted December 17, 2025, Claim Rejections - 35 USC § 103 segment beginning on page 10.
Applicant continues these assertions, stating “the Office also fails to establish that claims 1, 17-21, 32-36, 40, 44-49, 51-54 and 68-74 are prima facie obvious over Buchler, Clinical Trials.gov Identifier NCT02244632, and Fluorouracil Prescribing Information. Neither Buchler, Clinical Trials.gov Identifier NCT02244632 nor Fluorouracil Prescribing Information, either alone or in combination, disclose each element of the pending claims.”, see Remarks, page 11, 1st full paragraph (para.).
Applicant follows with arguments stating “Buchler does not disclose each element of independent claims 1 and 68” and fails to disclose claim elements and method steps, see page 11 of the Remarks. Applicant reasons the person of ordinary skill in the art (POSA) “…would have to make at least… nine separate modifications to Buchler to arrive at the claimed invention.”, see page 11, last complete sentence.
Applicant concludes these arguments stating how the Office has failed to provide explanations as to why or how the POSA would have been motivated to make changes with reasonable expectation of success utilizing the prior art references as the claimed invention yields “…significantly superior results…”, see pages 11-14. In particular, Applicant argues “…the ClinicalTrials.gov… does not disclose any combination treatment with bevacizumab, let alone a first step of administering bevacizumab or administration every 2 weeks.”, see page 12, 2nd para.
Applicant also argues the “Fluorouracil Prescribing Information does not disclose any combination treatment with bevacizumab, let alone a first step of administering bevacizumab or administration every 2 weeks.”, see sentence bridging pages 12 and 13 of the Remarks.
Applicant’s arguments and points have been carefully considered, however found unpersuasive.
It is not clear where this “actual posting date of September 8, 2020” is cited within the IDS reference, Record History of ClinicalTrials.gov Identifier NCT02244632 denoted as citation number 5 submitted December 17, 2025. It seems the ClinicalTrials.gov Identifier NCT02244632’s recruitment status is completed and a last update was posted on September 9, 2020 as cited below.
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This updated posting dated September 9, 2020 reflects “[t]he most recent date on which changes to a study record were available on ClinicalTrials.gov.” and does not preclude the study record version cited as prior art first posted September 19, 2014.
The Examiner has carefully reviewed IDS reference #5, as well as accessed the site where this information can be found online. Upon “clicking” on the hyperlink reading on 2014-09-17, one is directed to the Study Details with study status as one of the segments within.
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As of record on the ClinicalTrials.gov Identifier NCT02244632 document mailed to Applicant on November 27, 2024 with the first action on the merits (FAOM), the said document clearly cites on pages 1 and 2 of the nine pages, the information therein was first posted September 19, 2014. Hence, the information therein was of public record September 19, 2014 and prior to Applicant’s effective filing date, August 24, 2017.
The FAOM mailed November 27, 2024 clearly set forth how and why one of ordinary skill in the art would arrive at the claimed invention with a reasonable expectation of success with the combination of references herein, see rejection herein. Moreover, the ClinicalTrials makes clear the purpose of the study is to characterize the tolerability of the therapeutic agents, discern the best dose, as well as therapeutic combination of said agents for the treatment of colorectal cancer, see Descriptive Information bridging pages 3 and 4. Spectrum further highlights fluorouracil (5FU) is commonly administered in those individuals with gastric and colon cancers and recommended dose range for those stricken with said cancers. In addition, it is also clear from Buchler that the impetus to arrive at best treatment and clinical outcomes for metastatic colorectal cancer (mCRC) treatment has been an ongoing pursuit, see page 2, Background including citations therein.
And while the ClinicalTrials does not explicitly use bevacizumab in their combinatorial treatment as does Buchler, the ClinicalTrials does reference bevacizumab as a conceivable addition to the treatment combination, see ClinicalTrials, page 3, Brief Summary; page 4, Detailed Description; pages 4 and 5; and entirety of Buchler. Likewise, while the Fluorouracil reference does not explicity cite fluorouracil in combination with bevacizumab as does Buchler and as the ClinicalTrials cites an optional addition this does not preclude it use in combination with the monoclonal antibody, see Fluoruracil reference, page 2, segment 2.2.; entirety of Buchler; and ClinicalTrials, page 3, Brief Summary; page 4, Detailed Description; page 6.
One of ordinary skill in the art would have been motivated to administer the therapeutic agents within the particular administration order cited in the claims with a reasonable expectation of success by teachings well known and noted herein that dosages of any pharmaceutical composition may be adjusted and optimized. And while Applicant argues the particular order of administration and dosages of each of these agents is not taught by Buchler, one of ordinary skill in the art has been provided the general guidance and motivation to modify the combination of previously successful anti-cancer agents in light of the targeted treatment taught in all the references as the prior art leads a POSA to the parameters set forth in the claims. Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome.
"[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 233, 235(CCPA 1955).
The modification of the primary reference in light of the secondary references is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims obvious. For the reasons of record and cited herein, the rejection is maintained.
Buchler teaches treating metastatic colorectal carcinoma (mCRC) patient population with the initial administration of bevacizumab 5mg/kg intravenously (i.v.) followed with oxaliplatin 85 mg/m2 i.v., leucovorin (LV) 200 mg/m2 i.v. on days 1 and 2, 5-fluorouracil (5FU) 400 mg/ m2 i.v. bolus on days 1 and 2 and followed with an additional infusion of 5FU and compared to treating another mCRC patient population with bevacizumab, capecitabine and oxaliplatin, see title; and page 2, column 1, Patients…section.
Buchler does not teach folate, 6R-MTHF at a dose of 60 mg/ m2 was administered every 2 weeks by i.v. bolus between the two 5FU administrations with the second 5FU administration at an i.v. dose of 2,400 mg/ m2. Nor does Buchler teach leucovorin was administered at 400 mg/m2 i.v. and bevacizumab was administered every 2 weeks.
However, according to Buchler “[d]ose modifications were at the discretion of the attending oncologist”, hence adjustments to leucovorin and bevacizumab would have been reasonable to make, see page 2, Patients…section.
ClinicalTrials.gov Identifier NCT02244632 teaches modufolin also known as arfolitixorin, as well as 6R-MTHF is administered at dosages ranging from 30 to 240 mg/m2 in therapeutic combinations with chemotherapeutic agents (5-FU, oxaliplatin) and bevacizumab, see Detailed Description and Intervention sections on page 4. Absent evidence to the contrary, 6R-MTHF was provided at a diastereomeric purity of 98% or higher as a lyophilisate, prepared from hemisulfate salt and/or trisodium citrate dihydrate and reconstituted in aqueous media for administration.
Moreover, Spectrum Pharmaceuticals teaches administering an infusional regimen of 5FU in combination with other chemotherapeutic agents initially at 400 mg/ m2 i.v. bolus followed later by intravenous administration of 2400 mg/m2 to 3000 mg/m2, see page 2, section 2.2.
It would not be outside the scope of the skilled artisan to substitute first-line therapeutic for mCRC for another one. It is obvious to those skilled in the art to substitute one known equivalent for another. See In re Omeprazole Patent Litigation, 483 F.3d 1364, 1374 (Fed. Cir. 2007) (“[T]his court finds no . . . error in [the] conclusion that it would have been obvious to one skilled in the art to substitute one ARC [alkaline reactive compound] for another.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references in order to effectively discern and modify dosages to treat subjects with colorectal cancer with this particular combination of anti-colorectal cancer therapeutic agents, see all three references in their entirety and particularly, Buchler, Patients…section on page 2; ClinicalTrials, pages 2 and 3; and Spectrum, Dosage…on page 1. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in all references that the therapeutic agents taught herein have all be effective in colon cancer treatment and dose modifications are known to be at the discretion of the attending oncologist and arrived upon based on previously prescribed recommended targeted therapeutic modalities, see all three references in their entirety.
Claims 40, 45, 46, 48, 51-53, 69 and 71-74 set forth wherein clauses reading on changes in tumor size, tumor growth and survival responses are met once the therapeutic agents listed in claims 1 and 68 are administered and compared to those colorectal or mCRC treated with another combination of therapeutic agents including LV. The claims merely state the results or conclusion of the results of the administrations not tied to any machine and does not transform any article into a different state or thing. They simply express the intended results of the positively recited process steps, i.e. administering the agents denoted in claims 1, 47, 49, 54, 68 and 70.
7. The rejection of claims 1, 17-21, 32-36, 40, 44-49, 51-54 and 68-74 under 35 U.S.C. 103 as being unpatentable over Saif et al., (Clinical Colorectal Cancer 6(3): 229-234, September 2006/ IDS reference CG on sheet 3 submitted March 6, 2023), and further in view of ClinicalTrials.gov Identifier NCT02244632 (9 pages, publicly available September 19, 2014) and Spectrum Pharmaceuticals, Inc. (Fluorouracil injection, 8 pages, posted July 2016/ IDS reference CAA on sheet 5 submitted March 6, 2023) is maintained.
Applicant reiterates secondary reference, ClinicalTrials.gov Identifier NCT02244632 has an actual posting date of September 8, 2020 and the said ClinicalTrials.gov Identifier at most could only be afforded the date of August 30, 2016, see Remarks submitted December 17, 2026, page 15, 3rd paragraph (para.). Applicant further argues there are significant differences between the alleged September 8, 2020 entry and an alleged entry publicly available on August 30, 2016.
Applicant notes the teachings of Saif and then argues it does not disclose each element of independent claims 1 and 68, nor cite the claim elements and in particular, the limitations listed with the thirteen bullets cited on page 16 of the Remarks.
Applicant continues arguments alleging “the Office has not explained why or how the POSA would have been motivated to make each …[change] with a reasonable expectation of success, either alone or in combination with ClinicalTrials.gov Identifier NCT02244632 and/or Fluorouracil Prescribing Information.”, see the Remarks, page 16.
Applicant points out purported misgivings of each reference and concludes the Office has not provided any explanation or specific reasoning why or how the POSA would have selected or been motivated to arrive at the claimed inventions as the specification describes “…superior results…”, see the Remarks, pages 16-19. In particular, Applicant argues “…the ClinicalTrials.gov… does not disclose any combination treatment with bevacizumab, let alone a first step of administering bevacizumab.”, see page 17, lines 1-3.
Applicant also argues the “Fluorouracil Prescribing Information does not disclose any combination treatment with bevacizumab, let alone a first step of administering bevacizumab.”, see page 17, 1st full para. of the Remarks.
Applicant’s arguments and points have been carefully considered, however found unpersuasive.
As stated in the first pending 103 spanning pages 3-11, herein the information relied upon in the ClinicalTrials.gov Identifier NCT02244632 has been publicly available since its posted date of September 17, 2014, on page 1 and 2 of the document. Applicant has the point of view the “Last Update Posted” refers to an actual posting date, September 8, 2020. However, this date is not seen in the IDS reference, Record History of ClinicalTrials.gov Identifier NCT02244632 denoted as citation number 5 submitted December 17, 2025. Notwithstanding, the date has been properly identified as September 17, 2014 and is relevant as prior art as it is before Applicant’s effective filing date August 24, 2017 for the reasons of record herein and of record.
The first action on the merits (FAOM) mailed November 27, 2024 clearly sets forth how, why one of ordinary skill in the art would arrive at the claimed invention with a reasonable expectation of success with the combination of references herein, see last two paragraphs of rejection in said Action, as well as herein. Moreover, the ClinicalTrials makes clear the purpose of the study is to characterize the tolerability of the therapeutic agents, discern the best dose, as well as therapeutic combination of said agents, see Descriptive Information bridging pages 3 and 4. Spectrum further highlights fluorouracil (5FU) is commonly administered in those individuals with gastric and colon cancers and recommended dose range for those stricken with said cancers. In addition, it is also clear from Saif that the impetus to arrive at best treatment and clinical outcomes for metastatic colorectal cancer (mCRC) treatment has been an ongoing pursuit, see page 2, Background including citations therein.
And while the ClinicalTrials does not explicitly use bevacizumab in their combinatorial treatment as does Saif, the ClinicalTrials does reference bevacizumab as a conceivable addition to the treatment combination, see ClinicalTrials, page 3, Brief Summary; page 4, Detailed Description; pages 4 and 5; and entirety of Saif. Likewise, while the Fluorouracil reference does not explicitly cite fluorouracil in combination with bevacizumab as does Saif and as the ClinicalTrials cites an optional addition this does not preclude it use in combination with the monoclonal antibody, see Fluoruracil reference, page 2, segment 2.2.; entirety of Saif; and ClinicalTrials, page 3, Brief Summary; page 4, Detailed Description; page 6.
One of ordinary skill in the art would have been motivated to administer the therapeutic agents within the particular administration order cited within the claims with a reasonable expectation of success by teachings well known and noted herein that dosages of any pharmaceutical composition may be adjusted and optimized. And while Applicants argue the particular order of administration of each of these agents is not taught by Saif, one of ordinary skill in the art has been provided the general guidance and motivation to modify the combination of previously successful anti-cancer agents in light of the targeted treatment taught in all the references as the prior art leads a POSA to the parameters set forth in the claims. Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and
clinical outcome.
"[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 233, 235(CCPA 1955).
The modification of the primary reference in light of the secondary references is proper because the applied references are so related that the appearance of features shown in one would suggest the application of those features to the other. See In re Rosen, 673 F.2d 388, 213 USPQ 347 (CCPA 1982); In re Carter, 673 F.2d 1378, 213 USPQ 625 (CCPA 1982), and In re Glavas, 230 F.2d 447, 109 USPQ 50 (CCPA 1956). Further, it is noted that case law has held that a designer skilled in the art is charged with knowledge of the related art; therefore, the combination of old elements, herein, would have been well within the level of ordinary skill. See In re Antle, 444 F.2d 1168,170 USPQ 285 (CCPA 1971) and In re Nalbandian, 661 F.2d 1214, 211 USPQ 782 (CCPA 1981). The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims obvious. For the reasons of record and cited herein, the rejection is maintained.
Saif teaches treating one metastatic colorectal carcinoma patient group (Arm A) with CoFactor® (USAN fotrexorin calcium, also known as [dl]-5,10,-methylenetetrahydropteroyl-monoglutamate calcium salt and trivially as racemic CH2THF), fluoropyrimidine 5-fluoruracil (5-FU) and bevacizumab and another patient group with leucovorin (LV), 5-FU and bevacizumab, see title; and Figure 2 on page 232.
“CoFactor® will be administered at a dose of 60 mg/m2 over 2-3 minutes by I.V. bolus followed 20 minutes later by the administration of 5-FU as a bolus over 2-3 minutes at a dose of 500 mg/m2 each week for 6 weeks, repeated every 8 weeks. Bevacizumab will be administered at a dose of 5 mg/kg as a continuous I.V. over 90 minutes every 2 weeks. “, see bridging paragraph of pages 231 and 232.
Arm B patients received “[l]eucovorin will be administered at a dose of 500 mg/m2 I.V. over a 2-hour infusion. 5-Fluorouracil will be administered as a bolus over 2-3 minutes at a dose of 500 mg/m2 1 hour after the start of LV each week for 6 weeks, repeated every 8 weeks. Bevacizumab will be administered after 5-FU at a dose of 5 mg/kg as a continuous I.V. over 90 minutes every 2 weeks. A cycle of treatment under arm B is considered 8 weeks of treatment. Dosing in subsequent cycles should start as close as possible to 21 days after last dose of 5-FU in the previous cycle. Subjects will receive CoFactor®/5-FU (arm A) each week for the first 6 weeks of an 8-week cycle or LV/5-FU (arm B) each week for the first 6 weeks of an 8-week cycle. In addition, all subjects will receive bevacizumab every 2 weeks”, see page 232, Arm B section.
Saif does not teach oxaliplatin chemotherapy in a dose of 85 mg/m2 i.v. was administered in combination with the taught therapeutic combination, nor that the folate was 6R-MTHF and 5-FU was administered after 6R-MTHF at an i.v. bolus dosage of 2,400 mg/m2 and LV was 400 mg/m2 i.v.
However, ClinicalTrials.gov Identifier NCT02244632 teaches modufolin also known as arfolitixorin, as well as 6R-MTHF is administered at dosages ranging from 30 to 240 mg/m2 in therapeutic combinations with chemotherapeutic agents (5-FU, oxaliplatin) and bevacizumab, see Detailed Description and Intervention sections on page 4. Absent evidence to the contrary, 6R-MTHF was provided at a diastereomeric purity of 98% or higher as a lyophilisate, prepared from hemisulfate salt and/or trisodium citrate dihydrate and reconstituted in aqueous media for administration.
Moreover, Spectrum Pharmaceuticals teaches administering an infusional regimen of 5FU in combination with other chemotherapeutic agents initially at 400 mg/m2 i.v. bolus followed later by intravenous administration of 2400 mg/m2 to 3000 mg/m2, see page 2, section 2.2. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to substitute 6R-MTHF for CoFactor®, since both folate biomodulators are functionally related compounds and would be expected to share common properties (i.e. potentiates 5-FU cytotoxicity), see page 230 of Saif, 1st sentence in column 1.
It would not be outside the scope of the skilled artisan to substitute first-line therapeutic for mCRC for another one. It is obvious to those skilled in the art to substitute one known equivalent for another. See In re Omeprazole Patent Litigation, 483 F.3d 1364, 1374 (Fed. Cir. 2007) (“[T]his court finds no . . . error in [the] conclusion that it would have been obvious to one skilled in the art to substitute one ARC [alkaline reactive compound] for another.”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references in order to effectively discern, distinguish and modify dosages to treat subjects with colorectal cancer with the two different combinations of anti-colorectal cancer therapeutic agents, see all three references in their entirety and particularly, Saif, Preclinical Studies on page 230; ClinicalTrials, pages 2 and 3; and Spectrum, Dosage…on page 1. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in Saif and ClinicalTrials references that comparing and contrasting colon cancer treatment regimens is an effective means for determining the best clinical course of treatment and dose modifications are known to be routine in the art and essential for achieving and enhancing clinical activity, see all three references in their entirety.
Claims 40, 45, 46, 48, 51-53, 69 and 71-74 set forth wherein clauses reading on changes in tumor size, tumor growth and survival responses are met once the therapeutic agents listed in claims 1 and 68 are administered and compared to those colorectal or mCRC treated with another combination of therapeutic agents including LV. The claims merely state the results or conclusion of the results of the administrations not tied to any machine and does not transform any article into a different state or thing. They simply express the intended results of the positively recited process steps, i.e. administering the agents denoted in claims 1, 47, 49, 54, 68 and 70.
Double Patenting
8. 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.
9. The nonstatutory double patenting rejection over claims 1, 17-21, 32-36, 40, 44-49, 51-54 and 68-74 as being unpatentable over claims 1-8 of U.S. Patent No. 10,292,984 B2 (issued May 21, 2019) is maintained.
Applicant details the steps that govern an obviousness-type double patenting rejection and assert “…’984 patent [does] not disclose each element of the independent claims 1 and 68 of the present application.”, see Remarks submitted December 17, 2026, page 20 and page 21.
Applicant also argues the rejection has not provided to any reason or motivation to modify the methods of the patent to achieve the specific dosing regimen of the instant claims, see Remarks, paragraph (para.) bridging pages 21 and 22.
Applicant’s arguments and points of view have been carefully considered but fail to persuade.
At the onset of the instant rejection, it is recited “…the claims at issue are not identical”, however both sets of claims overlap in method steps and patient population. The Examiner has set forth articulate reasoning to support the combination of teachings, which provide scientific rationale and motivation for one of ordinary skill in the art to make modifications. The modification of these two sets of teachings is proper because the references are so related that the appearance of features shown in one would suggest the application of those features to the other. The Examiner recognizes that obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988) and In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Although the claims at issue are not identical, they are not patentably distinct from each other because both methods of treating read on treating colon cancer (CRC) and metastatic CRC with the same combination of anti-cancer therapeutic agents, 5-fluorouracil, [6R]-5,10-methylenetetrahydrofolate (6R-MTHF), oxaliplatin, bevacizumab and 5-formyl tetrahydrofolate (LV) also known as leucovorin.
U.S. Patent 10,292,984 does not teach the specific dosages listed in the claims.
However, Patent ‘984 does teach overlapping dosages. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the teachings of the reference in order to effectively discern, distinguish and modify dosages to treat subjects with colorectal cancer with the two clinical combinations of anti-colorectal cancer therapeutic agents. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in both documents to establish optimal therapeutic regimen.
Moreover, "where 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 233, 235(CCPA 1955). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings well known in the art, that dosages of any pharmaceutical composition must be adjusted and optimized to arrive at the desired result.
10. The nonstatutory double patenting rejection over claims 1, 17-21, 32-36, 40, 44, 45, 48, 49, 51-53, 68 and 69 as being unpatentable over claims 1-21 and 23 of U.S. Patent No. 10,328,079 B2 (issued June 25, 2019) is maintained.
Applicant details the steps that govern an obviousness-type double patenting rejection and assert “…’079 patent [does] not disclose each clement[sic] of the independent claims 1 and 68 of the present application.”, see Remarks submitted December 17, 2026, page 20, 6th paragraph (para.).
Applicant also argues the rejection has not provided to any reason or motivation to modify the methods of the patent to achieve the specific dosing regimen of the instant claims, see Remarks, last full para. on page 20.
Applicant’s arguments and points of view have been carefully considered but fail to persuade.
At the onset of the instant rejection, it is recited “…the claims at issue are not identical”, however both sets of claims overlap in method steps and patient population. The Examiner has set forth articulate reasoning to support the combination of teachings, which provide scientific rationale and motivation for one of ordinary skill in the art to make modifications. The modification of these two sets of teachings is proper because the references are so related that the appearance of features shown in one would suggest the application of those features to the other. The Examiner recognizes that obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988) and In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Both sets of claims read on treating colon cancer (CRC) and metastatic CRC with the same combination of anti-cancer therapeutic agents, 5-fluorouracil, [6R]-5,10-methylenetetrahydrofolate (6R-MTHF), oxaliplatin and bevacizumab.
U.S. Patent 10,328,079 does not teach the specific dosages listed in the instant claims.
However, Patent ‘079 does teach overlapping dosages. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the teachings of the reference in order to effectively discern, distinguish and modify dosages to treat subjects with colorectal cancer with the two clinical combinations of anti-colorectal cancer therapeutic agents. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in both documents to establish optimal therapeutic regimen.
Moreover, "where 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 233, 235(CCPA 1955). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings well known in the art, that dosages of any pharmaceutical composition must be adjusted and optimized to arrive at the desired result.
11. The nonstatutory double patenting rejection over claims 1, 17-21, 32-36, 40, 44-49, 51-54 and 68-74 as being unpatentable over claims 1-13 of U.S. Patent No. 10,639,311 B2 (issued May 5, 2020) is maintained.
Applicant details the steps that govern an obviousness-type double patenting rejection and assert “…’311 patent [does] not disclose each element of the independent claims 1 and 68 of the present application.”, see Remarks submitted December 17, 2026, page 21, 1st full paragraph (para.).
Applicant also argues the rejection has not provided to any reason or motivation to modify the methods of the patent to achieve the specific dosing regimen of the instant claims, see Remarks, 1st full para. on page 21.
Applicant’s arguments and points of view have been carefully considered but fail to persuade.
At the onset of the instant rejection, it is recited “…the claims at issue are not identical”, however both sets of claims overlap in method steps and patient population. The Examiner has set forth articulate reasoning to support the combination of teachings, which provide scientific rationale and motivation for one of ordinary skill in the art to make modifications. The modification of these two sets of teachings is proper because the references are so related that the appearance of features shown in one would suggest the application of those features to the other. The Examiner recognizes that obviousness can only be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988) and In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992). Adjustment of the dosing schedule would be within the purview of the clinician/scientist and reasonable to implement in order to reasonably to determine the best clinical practice, clinical parameters and clinical outcome. The combination of references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. For the reasons of record and cited herein, the rejection is maintained.
Both sets of claims read on methods of treating colon cancer (CRC) and metastatic CRC with the same combination of anti-cancer therapeutic agents, 5-fluorouracil, [6R]-5,10-methylenetetrahydrofolate (6R-MTHF), oxaliplatin, bevacizumab and 5-formyl tetrahydrofolate (LV) also known as leucovorin with the same and/or overlapping dosages. Moreover, both sets of claims also read on 6R-MTHF with the same and/or similar purity.
U.S. Patent 10,639,311 does not teach the specific dosages listed in the claims.
However, Patent ‘311 does teach overlapping dosages. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to implement the teachings of the reference in order to effectively discern, distinguish and modify dosages to treat subjects with colorectal cancer with the two clinical combinations of anti-colorectal cancer therapeutic agents. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in both documents to establish optimal therapeutic regimen.
Moreover, "where 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 233, 235(CCPA 1955). One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings well known in the art, that dosages of any pharmaceutical composition must be adjusted and optimized to arrive at the desired result.
Conclusion
12. All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) 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 nonprovisional extension fee (37 CFR 1.17(a)) 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.
13. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday and occasionally Saturday evening.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached on 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
23 January 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643