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
Claim Status
The claims filed October 6, 2023 have been received and entered.
Claims 1-14 are pending.
Claims 8-14 are objected to under 37 CFR 1.75(c) as being in improper form because a multiple dependent claim cannot depend from any other multiple dependent claim. See MPEP § 608.01(n). Accordingly, the claims have not been further treated on the merits.
Claims 1-7 are under examination.
Priority
The present application was filed on April 20, 2023.
Information Disclosure Statements
The information disclosure statements (IDSs) submitted on November 20, 2023 and November 5, 2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 7 is objected to because of the following informalities:
Claim 7 should read “according to any one of claims 5 or 6”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-7 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The claims as written can be interpreted as both a product and a method of using the product.
The claims recite “Arfolitixorin for use...” which suggests a product composition comprising arfolitixorin and administering an arfolitixorin composition in separate steps [claim 1, subparagraphs c) and g)]. Thus, it is unclear if the claims are intended to encompass a composition comprising arfolitixorin which has an intended use in the disclosed steps of a process of treating adenocarcinoma, or if the claims are intended to encompass a method of treating adenocarcinoma comprising the disclosed steps.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-7 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(1) as being anticipated by Lindberg et al. (US Patent No. 11,013,744) (“Lindberg”). This reference qualifies as prior art under both 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2).
As set forth in the 112 rejection above, the instant claims can be interpreted as both a product or a method. In the interest of compact prosecution, for the purposes of applying art, the claims have been construed as a product comprising arfolitixorin wherein the steps are intended use of the claimed composition.
Lindberg teaches the compound “arfolitixorin and [6R]-5,10-MTHF shall both refer to the single diastereomer, [6R]-5, 10-methylenetetrahydrofolate” [ page 4, col. 9-10].
The instant claims are directed to the use of arfolitixorin for the treatment of adenocarcinoma. However, such a limitation of the instant claims fail to patentably distinguish the instant claims over the cited prior art because such a limitation is an intended use of the composition (i.e., an intent to use the disclosed arfolitixorin in a regimen for the treatment of adenocarcinoma), which does not impart any physical or material characteristics to the composition that is not already present in the cited prior art.
In the instant case, the claims are directed to arfolitixorin and, thus, would be reasonably expected to be capable of performing the intended use as instantly claimed, absent factual evidence to the contrary and further absent any apparent structural difference between the composition of the prior art and that of the instant claims. Moreover, Lindberg teaches the treatment of solid tumors in humans such as cancer, which involves [6R]-5,10-methylenetetrahydrofolate ([6R]-MTHF) in 5- fluorouracil (5-FU) based chemotherapy [col. 1, lines 6-10]. Thus, Lindberg teaches the disclosed arfolitixorin is useful in a treatment regimen for adenocarcinoma. Therefore, absent a showing of any difference, the arfolotixorin product disclosed by the prior art is arfolotixorin for use in the steps recited in the present product claims.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 5-6 are rejected under 35 U.S.C. 103 as being unpatentable over Lindberg et al. (WO 2019/037898; cited on IDS 11/20/2023) (“Lindberg”) in view of Machover et al. (Sci Rep, 2021; 11(1):12668; cited on IDS 11/20/2023) (“Machover”).
As set forth in the 112 rejection above, the instant claims can be interpreted as a product or a method. In the interest of compact prosecution, for the purposes of applying art, the claims have been construed as a method of treating adenocarcinoma in a human patient comprising the disclosed steps, wherein the patient has RAS wild-type adenocarcinoma, or is KRAS-mutation positive.
Lindberg discloses the standard first-line adjuvant therapy of metastatic colorectal cancer includes single and combination chemotherapy with the agent 5-Fluorouracil (5-FU). Treatment with 5-FU is usually given in combination with high doses of folate (leucovorin) which significantly enhances the therapeutic effect of 5-FU in metastatic colorectal carcinoma [pg. 4, lines 20-30]. However, leucovorin needs to be converted to the active metabolite [6R]-5,10-methylenetetrahydrofolate ([6R-MTHF]), a process that varies between individuals and effects the overall response rate for 5-FU [pg. 5, lines 1-23]. Lindberg furth discloses that additional chemotherapeutic agents such as irinotecan, oxaliplatin, bevacizumab, cetuximab, and panitumumab are frequently administered alone or in combination with the first-line treatment of colorectal cancer.
Lindberg discloses a stable formulation of [6R]-MTHF that can be used to treat colorectal cancer patients in a variety of chemotherapeutic protocols involving initial administration of 5-FU resulting in objective response rates (ORR’s) of 50-60%. Moreover, [6R]-MTHF combined with 5-FU showed clinical benefit in colorectal cancer, defined as stable disease or tumor response, in greater than 90% of treated patients [pg. 8, lines 1-20].
Specifically, Lindberg teaches a method for treating solid tumors comprising a two day treatment cycle that may be repeated every 2 weeks for a total treatment period up to 16 weeks, wherein no statistically significant progression solid tumors is expected [pg. 17, lines 4-10; pg. 24, lines 30-33]. The treatment may further comprise administering one or more anticancer drugs on Day 1, either as an IV bolus or as an infusion over a period of 1-4 hours. Lindberg teaches anticancer drugs include monoclonal antibodies, such as cetuximab (Erbitux) and bevacizumab (Avastin).
Following administration of the anticancer drug on Day 1, 5-FU (10-1000 mg/m2) is administered simultaneously (or up to 4 hours after) with [6R]-MTHF (30, 60 or 120 mg/m2), followed by continuous infusion of 5-FU (10-1000 mg/m2) until the end of Day 2. An additional dose of [6R]-MTHF (30, 60 or 120 mg/m2) is administered on Day 2 [pg. 21-22].
Lindberg further evaluated the safety and efficacy of [6R]-MTHF (30-240 mg/m2) in combination with a fixed dose of 5-Fluorouracil (5-FU), bevacizumab (5 mg/kg; 90 min), oxaliplatin (85 mg/m2; 120 min), or irinotecan (180 mg/m2; 30 min) in patients with stage IV colorectal cancer [pg. 26].
The instant specification discloses that [6R]-5,10-methylenetetrahydrofolate is known as arfolitixorin (Modufolin) [pg. 7, lines 1-5].
One of ordinary skill in the art would readily envisage a method wherein oxaliplatin and irinotecan are administered prior to 5-FU since Lindberg teaches oxaliplatin and irinotecan as two of three drugs that can be the one or more anticancer drugs on Day 1.
Lindberg does not explicitly teach that the method includes the administration of pyridoxine or that the drugs are administered in the order as claimed.
Machover teaches first-line FOLFIRINOX treatment has proven efficacy in patients with advanced colorectal and pancreatic adenocarcinoma, with antitumor responses reported in approximately 30% of patients with pancreatic carcinoma and as high as 75% of patients with colorectal carcinoma. However, complete responses as well as partial responses of great magnitude are infrequent events in these patients [Discussion, pg. 6]. In the standard treatment, 5-FU is modulated by folinic acid, however, attempts at improving the anticancer effect by increasing the dosage or type of folinic acid has been unsuccessful. Machover conducted preliminary experiments wherein cancer cells exposed to 5-FU with high concentrations of the active form of vitamin B6, pyridoxal 5’-phosphate (PLP), and folinic acid strongly potentiated the cytotoxic activity of 5-FU. Machover further teaches mice administrated high dose B6 vitamer in the form of pyridoxamine or pyridoxine can modulate 5-FU in vivo resulting in enhanced antitumor effect [pg.1-2].
Machover further teaches advanced digestive tract carcinomas can be treated by supplementing the classical FOLFIRINOX triplet regimen (leucovorin (folinic acid), 5- FU, irinotecan, and oxaliplatin) with a high concentration of pyridoxine, the cofactor of vitamin B6. Addition of high-dose pyridoxine potentiates the cytotoxicity of 5-FU in a synergistic fashion [Abstract].
Machover conducted a trial with previously untreated patients having advanced metastatic colorectal adenocarcinoma (n=5) and pancreatic adenocarcinoma (n=5). Of the five patients with colorectal adenocarcinoma, two had adenocarcinoma with wild-type (WT) Ras, and three patients had tumors that carried activating K-Ras mutations [Patients, pg. 3].
Machover discloses a two day protocol (repeated every 14 days) comprising administration of oxaliplatin (85 mg/m2, Day 1), irinotecan (180 mg/m2, Day 1), leucovorin (200 mg/m2/day, Days 1 and 2), and 5-FU (1000 mg/m2/day, Days 1 and 2) distributed in one rapid IV injection (400 mg/m2/day), and one IV infusion during 22 h (600 mg/m2/day). Patients with Ras-WT colorectal carcinoma received the anti EGF-R chimeric monoclonal antibody cetuximab in addition to chemotherapy [pg. 4]. Pyridoxine was administered concurrently with 5-FU and leucovorin at a dose of 3000 mg/day [pg. 5].
Machover further discloses that of the five patients with colorectal adenocarcinoma, two attained a complete response and three had significant tumor reduction. Similarly, the two patients with pancreatic adenocarcinoma attained a complete response and three had significant tumor reduction [Results, pg. 5]. These results suggest that addition of high doses of vitamin B6 strongly enhances the antitumor activity of standard chemotherapy combination regimens comprising 5-FU and leucovorin [Discussion, pg. 5-6].
Thus, Machover establishes that it was known in the art to utilize pyridoxine in combination with oxaliplatin, irinotecan, and 5-FU for the treatment of adenocarcinoma.
With regard to the sequence of administration of the anticancer drugs, MPEP 2144.04 (I)(V)(C) states, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) found a prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps. See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results; In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930), selection of any order of mixing ingredients is prima facie obvious.
In the instant case, the cited art does not explicitly teach the anticancer drugs are administered in the order as claimed, however, because the art suggests administering the same anticancer drugs for the treatment of adenocarcinoma, selection of the order of administration is prima facie obvious absent new or unexpected results.
The amount and duration of the drugs administered in the proposed treatments are the same as recited in the instant claims except that Lindberg teaches administering 10-1000 mg/m2 of 5-FU and 85 mg/m2 of oxaliplatin.
MPEP 2144.05 states, In the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). In the instant case, the amounts of 5-FU taught by Lindberg and Machover overlap or lie within the claimed ranges.
Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties." In the instant case, the amount of oxaliplatin taught by Lindberg and Machover is slightly above the instantly claimed amount (85 mg/m2 vs. 80 mg/m2, however it is so close that prima facie one skilled in the art would have expected them to have the same properties.
Thus, it would have been obvious to one of ordinary skill in the art to utilize the amount of pyridoxine taught by Machover and the treatment regimen taught by Lindberg as a starting point for optimizing the amount and treatment regimen, with the goal of treating cancer, including colorectal adenocarcinomas, since Machover teaches that exposure of cancer cells to 5-FU and folinic acid with high concentration pyridoxal 5'-phosphate, the cofactor of vitamin B6, potentiates the cytotoxicity of 5-FU in a synergistic interaction mode, and because dosage and treatment regimen are result-effective variables, i.e., a variable that achieves a recognized result. Moreover, Machover teaches the method is useful for WT-RAS and KRAS-mutated carcinomas. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. See MPEP 2144.05 [R-2](ll)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). As such, the combination of prior art references would result in the practice of the methods recited in the instant claims with a reasonable expectation of success. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Lindberg et al. (WO 2019/037898; cited on IDS 11/20/2023) (“Lindberg”) in view of Machover et al. (Sci Rep, 2021; 11(1):12668; cited on IDS 11/20/2023) (“Machover”) as applied to claims 1-2 and 5-6 above, and further in view of FDA Notice “FDA approves new dosing regimen for cetuximab”; April 6, 2021.
As set forth in the 112 rejection above, the instant claims can be interpreted as a product or a method. In the interest of compact prosecution, for the purposes of applying art, the claims have been construed as a method of treating adenocarcinoma in a human patient comprising the disclosed steps, wherein on Day 1 a continuous IV infusion containing 500 mg/m2 cetuximab is administered over 100 min± 5 min.
The teachings of Lindberg and Machover are set forth above.
Lindberg teaches a cetuximab can be administered on Day 1, bit does not recite the dosage and duration.
On April 6, 2021, the Food and Drug Administration approved a new dosage regimen of 500 mg/m2 as a 120-minute intravenous infusion every two weeks (Q2W) for cetuximab (Erbitux, ImClone LLC) for patients with K-Ras wild-type, EGFR-expressing colorectal cancer. This approval provides for a biweekly dosage regimen option in addition to the previously approved weekly dosage regimen for the approved indications when cetuximab is used in combination with chemotherapy or as a single agent [par. 1-2].
It would have been prima facie obvious to the skilled artisan to obtain the dosing information for cetuximab for use in the method taught by Lindberg, especially since it is approved for the treatment of colorectal cancer in combination with chemotherapy. One of ordinary skill in the art would have been able to obtain current cetuximab FDA dosing and timing protocols for treating cancer from (i.e., https://www.fda.gov). One would have more than a reasonable expectation of success because the cetuximab dosing protocol is indicated for use in treating cancer, including colorectal cancer, when used in combination with chemotherapy. As such, the combination of prior art references provided a prima facie case of obviousness.
Claims 1, 5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Lindberg et al. (WO 2019/037898; cited on IDS 11/20/2023) (“Lindberg”), in view of Machover et al. (Sci Rep, 2021; 11(1):12668; cited on IDS 11/20/2023) (“Machover”), and further in view of FDA Notice “FDA approves new dosing regimen for cetuximab”; April 6, 2021, as applied to claims 1-3 and 5-6 above, and in further view of Glimelius et al. (Can Treat Rev, 2021; 98:1-9) (“Glimelius”).
As set forth in the 112 rejection above, the instant claims can be interpreted as a product or a method. In the interest of compact prosecution, for the purposes of applying art, the claims have been construed as a method of treating adenocarcinoma in a human patient comprising the disclosed steps, wherein the patient is BRAF-mutation positive.
The teachings of Lindberg and Machover are set forth above.
Lindberg and Machover do not teach the method for use with adenocarcinoma patients with a BRAF mutation.
Glimelius teaches systemic chemotherapy agents, such as irinotecan and oxaliplatin, can further increase the efficacy of 5-FU-based treatments in patients with metastatic colorectal cancer [Abstract]. Stratification of patients according to mutation status or expression levels of genes such as RAS and BRAF V600E are recommended in international guidelines. While tumors expressing wild-type RAS are responsive to anti-EGFR agents such as cetuximab and panitumumab, tumors displaying RAS mutations are resistant to anti-EGFR therapies. Therefore, cetuximab and panitumumab are restricted to patients with tumors expressing wild-type RAS. However, the anti-VEGF agent bevacizumab may be used independent of RAS mutation status. BRAF V600E-mutation generally means rapid progression and poor survival with less and/or shorter response to chemotherapy. Glimelius further teaches several cetuximab combination therapies have demonstrated significant efficacy in patients with BRAF V600E-mutations [pg. 1 and pg. 2, par. 1].
It would have been obvious to one of ordinary skill in the art to treat patients having BRAF-mutated colorectal adenocarcinoma with the treatment regimen comprising bevacizumab or cetuximab taught by Lindberg since Glimelius teaches that bevacizumab may be used independent of RAS mutation status and cetuximab combination therapies have significant efficacy in patients with BRAF V600E-mutations. One would be motivated to treat this patient population with the combined protocols of Lindberg and Machover because patients with BRAF V600E-mutation have limited available therapies and demonstrate rapid disease progression and poor survival with less and/or shorter response to chemotherapy. As such, the combination of prior art references would result in the practice of the methods recited in the instant claims with a reasonable expectation of success. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Double Patenting
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-7 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-10, and 14-15 of U.S. Patent No. 11,013,744 and claims 1-3, 5-15, and 23 of U.S. Patent No. US 10,328,079.
As set forth in the 112 rejection above, the instant claims can be interpreted as both a product or a method. In the interest of compact prosecution, for the purposes of the instant rejection, the claims have been construed as a product comprising arfolitixorin wherein the steps are intended use of the claimed composition.
Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims are directed to method of treating a solid tumor comprising administering [6R]-5, 10-methylenetetrahydrofolate ([6R]-5,10-MTHF). Thus, the previously allowed claims teach arfolitixorin for use in the treatment of cancer, including adenocarcinoma.
The instant claims are directed to a compound arfolitixorin or [6R]-5,10-MTHF or [6R]-5, 10-methylenetetrahydrofolate, which is useful for the treatment of cancer, including adenocarcinoma. Such a limitation fails to patentably distinguish the instant claims over the cited prior art because such a limitation is an intended use of the composition (i.e., an intent to use the disclosed arfolitixorin in a treatment regimen for the treatment of adenocarcinoma), which does not impart any physical or material characteristics to the composition that is not already present in the cited prior art. In the instant case, the claims are directed to arfolitixorin and, thus, would be reasonably expected to be capable of performing the intended use as instantly claimed, absent factual evidence to the contrary and further absent any apparent structural difference between the composition of the prior art and that of the instant claims. Thus, the compound of the issued claims would anticipate the instantly claimed compound.
Claims 1-2 and 5-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-10, and 14-15 of U.S. Patent No. 11,013,744, and claims 1-3, 5-15, and 23 of U.S. Patent No. US 10,328,079, in view of Machover et al. (Sci Rep, 2021; 11(1):12668; cited on IDS 11/20/2023) (“Machover”).
As set forth in the 112 rejection above, the instant claims can be interpreted as both a product or a method. In the interest of compact prosecution, for the purposes of the instant rejection, the claims have been construed as a method of treating adenocarcinoma comprising the disclosed steps.
Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims are directed to a method of use of arfolitixorin ([6R]-5,10-MTHF or [6R]-5, 10-methylenetetrahydrofolate) in a regimen with bevacizumab, oxaliplatin, irinotecan, and 5-fluorouracil (5-FU) in a human patient for the treatment of adenocarcinoma.
The instant claims differ from the issued claims in that they do not explicitly teach the method includes the administration of pyridoxine, dosing for oxaliplatin and irinotecan, or that the drugs are administered in the order as claimed. The patented claims are silent regarding adenocarcinoma mutation status.
However, Machover teaches administering oxaliplatin (85 mg/m2, Day 1), irinotecan (180 mg/m2, Day 1),5-FU (1000 mg/m2/day, Days 1 and 2) distributed in one rapid IV injection (400 mg/m2/day), and one IV infusion during 22 h (600 mg/m2/day), and pyridoxine (3000 mg/day, Days 1 and 2). Further, Machover teaches previously untreated patients with advanced metastatic colorectal adenocarcinoma with wild-type (WT) Ras and K-Ras mutations, wherein 40% attained a complete response and 60% had significant tumor reduction.
Although the previously issued claims do not teach the same amounts or sequence of administration, MPEP 2144.04 (I)(V)(C) states, Ex parte Rubin, 128 USPQ 440 (Bd. App. 1959) found a prior art reference disclosing a process of making a laminated sheet wherein a base sheet is first coated with a metallic film and thereafter impregnated with a thermosetting material was held to render prima facie obvious claims directed to a process of making a laminated sheet by reversing the order of the prior art process steps. See also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results; In re Gibson, 39 F.2d 975, 5 USPQ 230 (CCPA 1930), selection of any order of mixing ingredients is prima facie obvious.
Regarding the amounts administered, MPEP 2144.05 states, In the case where the claimed ranges overlap or lie inside ranges disclosed by the prior art a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003). In the instant case, the amounts of 5-FU taught by Lindberg and Machover overlap or lie within the claimed ranges.
Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985). "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties." In the instant case, the amount of oxaliplatin taught by Lindberg and Machover is slightly above the instantly claimed amount (85 mg/m2 vs. 80 mg/m2, however it is so close that prima facie one skilled in the art would have expected them to have the same properties.
Thus, it would have been obvious to one of ordinary skill in the art to utilize the amount of pyridoxine taught by Machover and the treatment regimen taught by Lindberg as a starting point for optimizing the amount and treatment regimen, with the goal of treating cancer, including colorectal adenocarcinomas, since Machover teaches that exposure of cancer cells to 5-FU and folinic acid with high concentration pyridoxal 5'-phosphate, the cofactor of vitamin B6, potentiates the cytotoxicity of 5-FU in a synergistic interaction mode, and because dosage and treatment regimen are result-effective variables, i.e., a variable that achieves a recognized result. Moreover, Machover teaches the method is useful for WT-RAS and KRAS-mutated carcinomas. Therefore, the determination of the optimum or workable dosages would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum or workable dosing regimen given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. See MPEP 2144.05 [R-2](ll)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). As such, the combination of prior art references would result in the practice of the methods recited in the instant claims with a reasonable expectation of success. As such, the instant claimed invention is an obvious modification of the claims of the issued claims in view of Machover.
Claims 1 and 3 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-10, and 14-15 of U.S. Patent No. 11,013,744 and claims 1-3, 5-15, and 23 of U.S. Patent No. US 10,328,079, in view of Lindberg et al. (WO 2019/037898; cited on IDS 11/20/2023) (“Lindberg”), further in view of Machover et al. (Sci Rep, 2021; 11(1):12668; cited on IDS 11/20/2023) (“Machover”), and in further of FDA Notice “FDA approves new dosing regimen for cetuximab”; April 6, 2021.
As set forth in the 112 rejection above, the instant claims can be interpreted as both a product or a method. In the interest of compact prosecution, for the purposes of the instant rejection, the claims have been construed as a method of treating adenocarcinoma comprising the disclosed steps.
Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims are directed to a method of use of arfolitixorin ([6R]-5,10-MTHF or [6R]-5, 10-methylenetetrahydrofolate) in a regimen with bevacizumab, oxaliplatin, irinotecan, and 5-fluorouracil (5-FU) in a human patient for the treatment of adenocarcinoma.
The instant claims differ from the issued claims in that they do not explicitly teach the method can be used with cetuximab.
However, Lindberg teaches a method comprising administering one or more anticancer drugs, including cetuximab can be administered on Day 1 of the treatment cycle, prior to any other drug administration. Lindberg is silent on dosing for cetuximab.
It would have been prima facie obvious to the skilled artisan to obtain the dosing information for cetuximab for use in the method taught by Lindberg, especially since it is approved for the treatment of colorectal cancer in combination with chemotherapy. One of ordinary skill in the art would have been able to obtain current cetuximab FDA dosing and timing protocols for treating cancer from (i.e., https://www.fda.gov). At the time of the instant invention the FDA approved dosing of 500 mg/m2 as a 120-minute intravenous infusion every two weeks (Q2W) for patients with K-Ras wild-type colorectal cancer for use as a monotherapy or in combination with chemotherapy. As such, the instant claimed invention is an obvious modification of the claims of the issued claims in view of Lindberg, Machover, and the FDA.
Claims 1, 3, 5, and 7 are rejected on the ground of nonstatutory double patenting as being unpatentable 1-2, 5-10, and 14-15 of U.S. Patent No. 11,013,744 and claims 1-3, 5-15, and 23 of U.S. Patent No. US 10,328,079, in view of Machover et al. (Sci Rep, 2021; 11(1):12668; cited on IDS 11/20/2023) (“Machover”), further in view of Glimelius et al. (Can Treat Rev, 2021; 98:1-9) (“Glimelius”), and in further view of FDA Notice “FDA approves new dosing regimen for cetuximab”; April 6, 2021.
As set forth in the 112 rejection above, the instant claims can be interpreted as both a product or a method. In the interest of compact prosecution, for the purposes of the instant rejection, the claims have been construed as a method of treating adenocarcinoma comprising the disclosed steps.
Although the claims at issue are not identical, they are not patentably distinct from each other because the issued claims are directed to a method of use of arfolitixorin ([6R]-5,10-MTHF or [6R]-5, 10-methylenetetrahydrofolate) in a regimen with bevacizumab, oxaliplatin, irinotecan, and 5-fluorouracil (5-FU) in a human patient for the treatment of adenocarcinoma.
The instant claims differ from the issued claims in that they do not explicitly the method for use with adenocarcinoma patients with a BRAF mutation.
However, Glimelius teaches systemic chemotherapy agents, such as irinotecan and oxaliplatin, can further increase the efficacy of 5-FU-based treatments in patients with metastatic colorectal cancer. Glimelius teaches mutation status dictates treatment options, wherein bevacizumab may be used independent of RAS mutation status and cetuximab combination therapies provide significant clinical benefit in patients with BRAF V600E-mutations.
Accordingly, it would have been obvious to one of ordinary skill in the art to treat patients having BRAF-mutated colorectal adenocarcinoma with the treatment regimen comprising bevacizumab or cetuximab since Glimelius teaches that bevacizumab may be used independent of RAS mutation status and cetuximab combination therapies have significant efficacy in patients with BRAF V600E-mutations. As such, the instant claimed invention is an obvious modification of the claims of the issued claims in view of Machover, Glimelius, and the FDA.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16, 19, 21, 25, 28-29, 34-38, and 43-44 of copending Application No. 17/059,379, claims 1-2, 5-6, 12-13, and 15-16 of copending Application No. 17/329,075, claims 1, 4-7, 9-15, and 24 of copending Application No. 17/488,120, claims 1, 17-20, 32-35, 44, 68, and 70 of copending Application No. 18/075,391, and claims 14-29 of copending Application No. 18/702,490.
As set forth in the 112 rejection above, the instant claims can be interpreted as both a product or a method. In the interest of compact prosecution, for the purposes of the instant rejection, the claims have been construed as a product comprising arfolitixorin wherein the steps are intended use of the claimed composition.
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims of the conflicting applications are directed to method of treating cancer comprising administering [6R]-5, 10-methylenetetrahydrofolate ([6R]-5,10-MTHF). Thus, the copending claims teach arfolitixorin for use in the treatment of cancer, including adenocarcinoma.
The instant claims are directed to a compound arfolitixorin or [6R]-5,10-MTHF or [6R]-5, 10-methylenetetrahydrofolate, which is useful for the treatment of cancer, including adenocarcinoma. Such a limitation fails to patentably distinguish the instant claims over the copending claims because such a limitation is an intended use of the composition (i.e., an intent to use the disclosed arfolitixorin in a treatment regimen for the treatment of adenocarcinoma), which does not impart any physical or material characteristics to the composition that is not already present in the prior art. In the instant case, the claims are directed to arfolitixorin and, thus, would be reasonably expected to be capable of performing the intended use as instantly claimed, absent factual evidence to the contrary and further absent any apparent structural difference between the composition of the copending claims and that of the instant claims. Thus, the compound of the copending claims would anticipate the instantly claimed compound.
This is a provisional nonstatutory double patenting rejection.
Claims 1-7 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 5-6, and 15-16 of copending Application No. 17/329,075, claims 1, 4-7, 9, and 24 of 17/488,120, claims 1, 44, 68, and 70 of copending Application No. 18/075,391, and claims 25-29 of copending Application No. 18/702,490, (“Reference Applications”), in view of Lindberg et al. (WO 2019/037898), Machover et al. (2021), FDA Notice (April 6, 2021), and/or Glimelius et al. (2021).
As set forth in the 112 rejection above, the instant claims can be interpreted as both a product or a method. In the interest of compact prosecution, for the purposes of the instant rejection, the claims have been construed as a method of treating adenocarcinoma comprising the disclosed steps.
At least one instant 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) in view of Lindberg, Machover, the FDA, and/or Glimelius.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644