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
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 01/27/2025, wherein claims 37-38 and 43-44 are canceled. The cancellation of claims 37-38 and 43-44 overcome the objections to duplicative claims on the record. Applicant's amendment necessitated new ground rejection under 35 USC§112(b).
Election/Restrictions
Applicant elected Group II, method of treating cancer, with traverse in the reply filed on 11/20/2023.
Status of Claims
Claims 16, 17, 19, 21, 22, 24-29, 34-36 and 41 are pending.
Claims 16, 17, 19, 21, 22 and 24-27 remain withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
Claims 28, 29, 34-36 and 41 are currently under examination in this office action.
Action Summary
The Declaration under 37 CFR 1.132 by Dr. David Machover and Applicant’s Remarks filed 12/11/2025 have been fully considered. Any objections and rejections found in the previous Office Action and not repeated herein has been withdrawn based upon Applicant’s amendments to the claims. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
As necessitated by amendment, claims 28, 29, 34-36 and 41 are newly rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter.
Applicant’s arguments with respect to rejections under 35 USC§112(a) and 35 USC. § 103 have been fully considered, but they are NOT persuasive. The Scope of Enablement rejection under 35 USC 112(a) is maintained. Please see Response to Declaration.
Claims 28, 29, 34-36 and 41 rejected under 35 USC 103 as being unpatentable over Mortimer (1990), in view of Machover ‘2001 and Matsubara (2003) is maintained and reiterated as necessitated by amendment. Please note obviousness analysis is based on the combined teachings of prior art, together with general knowledge of fluoropyrimidine, folate, B6 vitamer and cancer treatment. Applicant’s argument against individual reference on the record are addressed accordingly.
Response to Declaration
The Declaration under 37 CFR 1.132 by Dr. David Machover filed 12/11/2025 is fully considered, but it’s NOT persuasive to overcome the scope of enablement rejection under 35 U.S.C. §112(a).
Machover Declaration elaborated on the mechanism and rationale for anti-tumor combinations enabling optimal thymidylate synthase TS inhibition by FUra :“The rationale behind the claimed invention is to obtain the greatest possible increase for the longest possible duration of tetrahydro pteroylglutamate (H4PteGlu), the only folate capable of forming an inactive complex with TS. The present application arises from the breakthrough hypothesis that the cytotoxic activity of FUra with reduced folates could be increased by addition of pyridoxal 5'phosphate (PLP), the active cofactor of vitamin B6, resulting from the enzymatic conversion of unphosphorylated and phosphorylated B6 vitamers (Declaration, pages 2-4).
RESPONSE: The Examiner does not dispute the proposed mechanism/ alternative rationale of instant combination of fluoropyrimidine/ B6 vitamer and folate. There are vast variety of enzyme target with variety of mechanism in cancer treatment. As explained in previous office action and reiterated in this office action, recitation of “increasing cytotoxic activity of fluoropyrimidine in a subject in need thereof” and wherein“ the cytotoxic activity of the fluoropyrimidine with the folate is enhanced by the parenteral administration of the B6 vitamer” in instant claims are construed as expression of intended function/result of administering a pharmaceutical combination/composition comprising fluoropyrimidine, B6 vitamer and folate, which do not necessarily materially differentiate instant claimed method from prior arts since such limitations do not result in manipulative difference in method steps of administering a pharmaceutical combination comprising fluoropyrimidine, folate and B6 vitamer based on the combined teachings of prior art and general knowledge of fluoropyrimidine, folate, B6 vitamer and cancer treatment. As stated in MPEP 2111.04: “the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Further, Machover’ 2001 on the record already teaches potentiation/synergism of the cytotoxic activity of 5-fluorouracil (FUra) by folinic acid (5-HCO-H4folate) is due to elevation of the methylene tetrahydrofolate (CH2-H4folate) level, which increases the stability of the ternary complex of thymidylate synthase (TS).
Machover Declaration argues unexpected enhancement of the cytotoxicity of FUra by folinic acid and PLP combined in certain cancer cells and later clinical result disclosed by Machover I, II, III, “The person skilled in the art would necessarily deduce that commonly known chemical or functional equivalents of the FU, folates and B6 vitamers other than those for which the invention has proven its effectiveness can also be successfully used because due to their known properties and potential for use, they are highly likely to perform the same function and would have no undue burden to overcome to implement the invention... Based on the mechanism of cytotoxicity of the fluoropyrimidines, it is also expected that the modulation of FUra by folates and B6 vitamers in tandem would result in improved cytotoxic activity in all tumors in which FUra has shown therapeutic activity”(Declaration, page 6).
RESPONSE: Applicant’s argument is fully considered, but NOT persuasive. Please note this is a SCOPE of enablement rejection. Instant specification discloses in-vitro cytotoxicity studies for combination of 5-fluorouracil/ [6S]-5-formyltetrahydrofolate/ pyridoxine or pyridoxamine on three cell lines (human colorectal carcinoma cell lines HT29 and HCT116 and murine L1210 lymphocytic leukemia), wherein the cytotoxicity of FUra are increased with a few combination of FUra-PLP-FA. Accordingly, instant claims is enabled for a method of increasing cytotoxic activity of FUra with specific combination of FUra-PLP-FA at specific amount in certain cancer treatment. However, instant claims are still directed to combination genus wherein fluoropyrimidine genus consists of 5-fluorouracil, capecitabine, 5-fluoro-2'- deoxyuridine, although instant claims are amended to a shortened list of folates (e.g. 5,10-methylenetetrahydrofolate) and B6 vitamers (e.g. 5'- phosphorylated derivatives), Instant specification does NOT disclose any working example for combination comprising capecitabine or 5-fluoro-2'- deoxyuridine or 5,10-methylenetetrahydrofolate. Capecitabine and 5-fluorouracil have different structures, different activity, different pharmacokinetic profile and different interaction with different folate and vitamin B6. It’s well-known cytotoxicity in cancer treatment is highly unpredictable as elaborated in 112(a) rejection on the record and there are vast variety of enzyme target with variety of mechanism. Applicant’s argument about the “prejudice” based on serine hydroxymethyltransferase (SHMT) associated with vitamin B6 against addition of vitamin B6 to anti-cancer combination in Remarks (page 24-30) further demonstrate the high unpredictability of cancer treatment. Instantly claimed high/elevated concentration of plasma B6(pyridoxine) might also have detrimental effect itself on the subject.
The general statement of mechanism or proposed rationale does not enable the full scope of instant claims. Later publications Machover I, II, III (published in 2021, 2022 and 2024) cannot be used to substitute for adequate disclosure of instant claimed invention at the time of filing. In absence of sufficient cytotoxic activity data for other combination, e.g. capecitabine/folate/B6 vitamer by instant disclosure, instant alleged effect of high doses of a B6 vitamer on combination genus fluoropyrimidines/folate/B6 vitamer is not fully supported/enabled. In other words , the alleged unexpected result/increased cytotoxicity is not commensurate with the scope of instantly claimed combination genus and instant disclosure.
Claim Interpretation
Independent claim 28 is amended to a method for increasing cytotoxic activity of fluoropyrimidine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of (i) a fluoropyrimidine, (ii) a B6 vitamer and (iii) a folate, wherein the fluoropyrimidine is selected from… the folate is selected from …the B6 vitamer is selected from… and wherein the cytotoxic activity of the fluoropyrimidine with the folate is enhanced by the parenteral administration of the B6 vitamer at a dose higher than 300 mg/day. Under the broadest reasonable interpretation (BRI), claim 28 is interpreted as pharmaceutical combination comprising (i) a fluoropyrimidine, (ii) a B6 vitamer and (iii) a folate. As disclosed by instant specification, the present invention relates to pharmaceutical compositions or combination comprising (i) a fluoropyrimidine, (ii) a B6 vitamer, and optionally (iii) a folate (See PGPub US 2021/0213020 A1, [0007]-[0009]).
The preamble “increasing cytotoxic activity of fluoropyrimidine in a subject in need thereof” and limitation wherein“ the cytotoxic activity of the fluoropyrimidine with the folate is enhanced by the parenteral administration of the B6 vitamer at a dose higher than 300 mg/day” in claim 28 and its dependent claims are construed as expression of intended function/result of administering a pharmaceutical combination/composition comprising fluoropyrimidine, B6 vitamer and folate. As stated in MPEP 2111.04 I: “the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Please note recitation of intended results of increasing cytotoxic activity of fluoropyrimidine in a subject in need thereof, do not necessarily or materially differentiate instant claimed method from prior art since such limitations do not result in manipulative difference in method steps of administering a pharmaceutical combination comprising fluoropyrimidine, folate and B6 vitamer. Instant claims only recite the subject in need thereof, but do not specifically recite what subject would be in need of “increasing cytotoxic activity of fluoropyrimidine”. The active ingredient fluoropyrimidines are well-known anti-tumor/cancer drug , and instant specification disclosed the present invention relates to methods for treating cancer in a subject in need thereof with pharmaceutical compositions or combination comprising (i) a fluoropyrimidine, (ii) a B6 vitamer, and optionally (iii) a folate( See PGPub US 2021/0213020 A1, [0007]-[0009], [0023]) and “the term "subject" denotes a mammal. Typically, a subject according to the invention refers to any subject (preferably human) afflicted or at risk to be afflicted with cancer” (See [0072]). Under broadest reasonable interpretation in the light of the specification, instant claims are construed as a method comprising administering a pharmaceutical combination comprising fluoropyrimidine, folate and B6 vitamer to a subject afflicted or at risk to be afflicted with cancer, wherein the intended function/ result of increasing cytotoxic activity of fluoropyrimidine by administering the pharmaceutical combination/composition is not given patentable weight in absence of evidence to the contrary.
Please note biological/pharmaceutical activities are the properties of a pharmaceutical combination/composition comprising fluoropyrimidine, folate and B6 vitamer, and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances. “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir.1999).
Priority
This application 17/059, 379 filed on November 27, 2020 is the U.S. national phase of International Application No. PCT/EP2019/063936 filed May 29, 2019 which designated the U.S. and claims priority to EP Patent Application No. 18305661.3 filed May 30, 2018.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 28, 29, 34-36 and 41 are rejected under 35 U.S.C. 112(a), because the specification, while might be enabling for a method of increasing cytotoxic activity of specific fluoropyrimidine(e.g. 5-fluorouracil) with specific combination of fluoropyrimidine, folate and B6 vitamer (e.g. FUra-FA-PLP), does not reasonably provide enablement for method of increasing cytotoxic activity of any recited fluoropyrimidine with any combination of recited fluoropyrimidine, B6 vitamer and folate. The specification does not enable a person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
Independent claims 28 and its dependent claims are amended to a method for increasing cytotoxic activity of fluoropyrimidine in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of pharmaceutical composition or combination comprising (i) a fluoropyrimidine, (ii) a B6 vitamer and (iii) a folate, wherein the fluoropyrimidine is selected … the folate is selected from …the B6 vitamer is selected from… and wherein the cytotoxic activity of the fluoropyrimidine with the folate is enhanced by the parenteral administration of the B6 vitamer at a dose higher than 300 mg/day.
Instant claims are construed under BRI as directed to a method for increasing cytotoxic activity of any recited fluoropyrimidine in any subject afflicted with cancer, by administering any combination genus comprising various combination, wherein any recited fluoropyrimidine could be combined with different folate and different B6 vitamer in different amount / concentration/ratio that could be administered in different route sequentially, or concomitantly.
Instant specification discloses in-vitro cytotoxicity studies of three cell lines (human colorectal carcinoma cell lines HT29 and HCT116 and murine L1210 lymphocytic leukemia) with a few combination of FUra-PLP-FA, where the cytotoxicity of FUra are increased. Accordingly, instant claims might be enabled for a method of increasing cytotoxic activity of FUra with combination of FUra-PLP-FA. However, instant claims referring to method of increasing cytotoxic activity of any recited fluoropyrimidine with any combination of recited B6 vitamer and folate in indefinite amount are extremely broad in contrast with the instant specification which only discloses in-vitro cytotoxicity studies of three cell lines with a few combination of FUra-PLP-FA.
The State of the Prior Art and the Predictability or Lack Thereof in the Art
It is well known in the art that biological activity (e.g. cytotoxic activity) of active drug and combination thereof is highly unpredictable and activity by in-vitro experiment does not necessarily translate into efficacy in animals and/or humans. When anticancer agents or combination thereof display in-vitro cytotoxic activity, the efficacy/effectiveness of treatment needs to be evaluated/validated through animal study and/or clinical study to provide accurate evidence for effective and safe cancer treatments in mammals /human which are not disclosed in instant specification.
Different fluoropyrimidine has different chemical structure, different physical properties, different pharmacological activity/cytotoxicity, different pharmacokinetic and pharmacodynamic profile, different toxicity profile and different interaction with different folate and B6 vitamer. Even when the same B6 vitamer (e.g. PLP) is administrated parenterally in the same amount in combination with different fluoropyrimidine, the combination would have different interaction/bioavailability, different pharmacokinetic profile, different level of PLP and different effect on the fluoropyrimidine, let alone combining different B6 vitamer together with different fluoropyrimidine, further in combination with different folate.
Regarding the method of increasing cytotoxic activity of fluoropyrimidine with combination of folates and other agents, folates (e.g. leucovorin LV) is widely studied in combination with 5-fluorouracil/ 5-FU in cancer treatment (e.g. colorectal cancer ) as demonstrated in Mortimer (1990) and Machover ‘2001, etc. Machover ‘2001 further teaches the potential mechanism of cytotoxic synergism of methioninase in combination with 5-fluorouracil and folinic acid. However, the enhancement/increase of 5-fluorouracil cytotoxic activity by folate is unpredictable due to a variety of factors, e.g. cancer cells, dosage of folates/fluoropyrimidine, unpredictable PK/PD profile, etc. As disclosed by Machover 2018(See Introduction): “Effectiveness of the biochemical modulation of the fluoropyrimidines by folates varies among cancer cells. Variation is thought to be due to differences in capacities for polyglutamation (Romanini et al., 1991) and for expansion of CH2-H4PteGlu pools. From results of prior reports, it is unlikely that supplementation of cancer cells with any amount of folate would result in rise of CH2-H4PteGlu to concentrations required to increase the tightness of FdUMP binding to TS for maximum stability of the ternary complex. In most of these studies when cancer cells were exposed to folates in great amounts, only limited increase of CH2-H4PteGlu concentration occurred, followed by rapid decline after discontinuation of folate exposure”. Further, enhancement of fluoropyrimidine cytotoxicity in combination with folates are often associated with unpredictable adverse event (e.g. Hand-foot syndrome) in cancer treatment as demonstrated in Mortimer .
Regarding the combination of fluoropyrimidine and B6 vitamer, Littman (Nature,1961) teaches vitamin B6 (e.g. pyridoxamine, pyridoxine) reversed 5-FU and 5-FUDR inhibition of Candida. albicans cell, an endogenous organism that bears close association with both normal and cancerous human host (See page 1157, Figures 3, 4, 5 ). The antagonism between B6 vitamer and 5-fluoropyrimidines taught by Littman is contradictory with instantly claimed synergistic effect of combination comprising 5-fluoropyrimidines and B6 vitamer, or at least raised question of uncertainty/unpredictability whether instant claimed combination could increase cytotoxicity of 5-fluoropyrimidines by adding high dose of vitamin B6 and/or the relative ratio of 5-fluoropyrimidines and vitamin B6. Please note the uncertainty of B6 vitamer pyridoxine in combination with capecitabine are also disclosed by Corrie (2012) and Chalermchai (2010) cited by Applicant, wherein significantly lower tumour responses to capecitabine at the higher pyridoxine dose level indicates pyridoxine might negatively influence on chemotherapy efficacy (cytotoxic activity of capecitabine), especially at higher dose.
Instant claim 41 recites limitation wherein the B6 vitamer is administered at a high dose enabling to achieve plasma and/or intracellular levels of PLP equal or greater than that required for optimum synergistic effect of the fluoropyrimidines. However, the plasma and/or intracellular levels of fluoropyrimidines, PLP and B6 vitamer in different subjects are unpredictable because different fluoropyrimidine has different pharmacokinetic and pharmacodynamic profile and different interaction with different folate and B6 vitamer. For example, parental administration of >300mg of pyridoxine or pyridoxamine in combination with specific folate at certain amount/dosage might increase cytotoxic effect of 5-FU, but might not increase cytotoxic activity of other fluopyrimidine drug ( e.g. capecitabine ) because pharmacokinetic and pharmacodynamic profile of different fluopyrimidine would be different. Further, instantly claimed high/elevated concentration of plasma B6(pyridoxine) might have detrimental effect itself on the subject, leading to a range of side effects and adverse events associated with vitamin B6 toxicity or pyridoxine toxicity, e.g. peripheral neuropathy/nerve damage affecting the limbs. See Vrolijk (2017, Toxicology in Vitro, The vitamin B6 paradox: Supplementation with high concentrations of pyridoxine leads to decreased vitamin B6 function).
As disclosed by instant specification (See [0132]-[0134]), “Although the present results fit our assumption, determination of the precise mechanism of the interaction is essential and demands further research. From our data, we hypothesize that vitamin B6 facilitates expansion of CH2 -H4PteGlu in cancer cells leading to increased ternary complex stabilization in the presence of FUra… neither intracellular concentration levels attained after incubation with high concentration PLP, nor metabolism of incorporated cofactor have been studied under these conditions ”.
As acknowledged by Machover ’ 2021 which further explored combination of 5‑fluorouracil , folinic acid and high‑dose pyridoxine for treatment of patients with digestive tract carcinomas (See page 7 of 11): “The present preliminary study does not enable correlating the magnitude of antitumor responses nor the rapidity to attain a response with the median daily dose of pyridoxine preceding each injection of FUra and FA received by each patient during the time of treatment (Table 2). Larger trials including dose finding studies are necessary to explore this issue…Owing to the limited number of patients entered in the present pilot study, further investigations are needed to demonstrate our findings. Exploring potentiation of FUra by FA and high dose B6 vitamer in tandem requires a first step of phase II trials in patients with potentially FUra-sensitive carcinomas. Vitamin B6 pharmacokinetic and dose-finding studies with emphasis on intracellular PLP levels, should accompany these trials to optimize the modulation of the fluoropyrimidines in accordance with experimental data”.
More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
As such, instantly claimed method of increasing cytotoxic activity of fluoropyrimidines genus by administering combination genus comprising various combination of fluoropyrimidines, folate and B6 vitamer is highly unpredictable, and with potential detrimental adverse effect of B6 toxicity and other unpredictable adverse effect associated with increased cytotoxicity of fluoropyrimidines.
The Amount of Direction Present and Presence or Absence of Working Examples
Instantly disclosed examples are only directed to in-vitro cytotoxicity studies of three cell lines( human colorectal carcinoma cell lines HT29 and HCT116 and murine L1210 lymphocytic leukemia) with a few combination of FUra-PLP-FA (See Spec page 28, Table 1). There are no examples of other cancer cells with other combination of fluoropyrimidine, B6 vitamer and folate for increasing cytotoxic effect of other recited fluoropyridine(e.g. capecitabine, etc.). There is no working example or data with any other combination of fluoropyrimidine, B6 vitamer and folate in the specification to provide a nexus between those working examples and increasing the cytotoxic activity for other fluoropyrimidine that have different pharmacokinetic and pharmacodynamic profile and different interaction with different folate and B6 vitamer. No direction or examples are provided for in-vivo study of any cancer with any combination of fluoropyrimidine, B6 vitamer and folate at a therapeutically effective amount to prevent potential adverse event due to the alleged increased cytotoxicity of fluoropyrimidine.
The level of one of ordinary skill in the art
The level of skill required to make and/or use the instant invention would likely require years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, medicinal chemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention.
The quantity of experimentation needed
An unduly extensive amount of experimentation would be required for one of ordinary skill in the art to practice instant claimed method of increasing cytotoxic activity of any recited fluoropyrimidine with any combination genus comprising various combination wherein any recited fluoropyrimidine (e.g. capecitabine) could be combined with different folate and B6 vitamer in its full scope. Working examples would be needed to determine how to combine different species of fluoropyrimidine, B6 vitamer and folate in what amount/concentration, ratio, administration route, etc.. Working examples would be needed to determine the therapeutically effective dose/plasma concentration of fluoropyrimidine/folate/B6 with different combination of fluoropyrimidine, B6 vitamer and folate respectively. The therapeutically effective amount may vary depending on many factors, such as the different combination comprising different fluoropyrimidine, B6 vitamer and folate by different administration route, the subjects being administered to, etc. Furthermore, the specific dosage may vary depending on the compound/combination selected, the dosing regimen to be followed and administration route, etc.
As such, it would be a great burden for one of ordinary skill in the art to carry out undue experimentation to use instant claimed method of increasing cytotoxic activity with any combination of fluoropyrimidine, B6 vitamer and folate in full scope.
Conclusion
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here with respect to the claimed method for increasing cytotoxic activity of any recited fluoropyrimidine with any combination of fluoropyrimidine, B6 vitamer and folate in full scope, in view of the analysis above pursuant to In re Wands. In other words, one skilled in the art could not practice the claimed invention without undue experimentation.
Response to Arguments
Applicant’s argument regarding the scope of enablement rejection is same as Dr. Machover’s Declaration. Please see Response to Declaration. The examiner does not dispute combination of [6S]-5 formyltetrahydrofolate and parenteral administration of high dose of pyridoxine and/or pyridoxamine (>300mg/day) might increase the cytotoxic effect of 5-fluorouracil. Applicant is advised to amend the scope of combination comprising fluoropyrimidine, B6 vitamer and folate to specific combination, e.g. FUra-FA-PLP with dosage/administration limitation and defined subject, that aligns with instant disclosure.
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 28, 29, 34-36 and 41 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention (newly applied as necessitated by amendment).
Independent claim 28 is amended to recite a method for increasing cytotoxic activity of fluoropyrimidine in a subject in need thereof comprising (i) a fluoropyrimidine, (ii) a B6 vitamer, and (iii) a folate, wherein the fluoropyrimidine is selected … the folate is selected from …the B6 vitamer is selected from…wherein the fluoropyrimidine is administered by one or more doses of up to 2400 mg/m2, the folate is administered at a dose equal to or higher than 200 mg/m2/day and the cytotoxic activity of the fluoropyrimidine with the folate is enhanced by the parenteral administration of the B6 vitamer at a dose higher than 300 mg/day.
The amended limitation of fluoropyrimidine administered by one or more doses of up to 2400 mg/m2 is indefinite. It’s not clear how many doses of fluoropyrimidine at what dose amount could be administered, 800mg/m2 administered one, two or three times?
The amended amount for the folate administered at a dose equal to or higher than 200 mg/m2/day is indefinite. The term “higher than” is relative and instant specification does not define the amount higher than higher than 200 mg/ m2/day. Is the folate administered at 400mg/ m2/day or 800 mg/m2/day or higher?
The parenteral administration of B6 vitamer at a dose higher than 300 mg/day is also indefinite and lacks sufficient support by instant specification. Instant specification only disclosed “conventional doses of B6 vitamers used to treat B6 vitamin deficiency are 1.3-300 mg/day, more particularly 50-300 mg/day. (See[0031]). Instant specification does NOT disclose any embodiment/working example of administering B6 vitamin at higher than 300mg/day.
The preamble “increasing cytotoxic activity of fluoropyrimidine” and the limitation ‘wherein the cytotoxic activity of the fluoropyrimidine with the folate is enhanced by the parenteral administration of the B6 vitamer” are confusing. The cytotoxic activity of different fluoropyrimidine and combination thereof is different. Is the increase/enhancement based on cytotoxic activity of fluoropyrimidine or cytotoxic activity of fluoropyrimidine in combination with folate? The term “increasing” and “enhanced” are relative term and indefinite regarding the degree of increase/ enhancement of cytotoxic activity of different fluoropyrimidine or combination thereof, What’s the threshold/ percentage of difference in cytotoxicity is considered as increase, 5%, 10%, 20% or 30%?
Dependent claims 29, 34-36 and 41 are also rejected due to their dependency on claim 28.
Amended claim 29 recites “wherein is administered simultaneously, separately or sequentially”. The subject is missing before “is administered”. It’s not clear what is administered to the subject in need thereof.
Claims 34 recites “wherein the composition is administered sequentially or concomitantly with one or more immunotherapeutic, chemotherapeutic or radiotherapeutic agents”. Claim 28 is amended by removing “ a composition” , thus, “the composition” in claim 34 lacks antecedent basis.
Claim 36 recites limitation wherein “the composition is in one dosage unit form or the combination comprises a kit of parts where the fluoropyrimidine, the B6 vitamer and the folate are administered independently at the same time or separately within time intervals that allow that the combination partners show a synergistic effect”. First, claim 28 is amended by removing “ a composition” , thus, “the composition” in claim 36 lacks antecedent basis. Second, the administration order, and time intervals of administering combination of fluoropyrimidine, B6 vitamer and folate are not defined by instant specification. A person of ordinary skilled in the art would not know what “combination partners” following what administration order and at “what time intervals to administered” to achieve the alleged “synergistic effect”. The pharmacokinetic profile of different fluoropyrimidine, B6 vitamer and folate would be different, even the same combination of fluoropyrimidine, B6 vitamer and folate administered at different time, and/or at different time intervals would have different effect on the cytotoxic activity of fluoropyrimidine.
Claim 41 recites the method according to claim 28, wherein “the B6 vitamer is administered at a dose enabling to achieve plasma and/or intracellular levels of PLP equal or greater than that required for synergistic effect of the fluoropyrimidines”. The term “enabling”, “equal or greater than” “synergistic effect of the fluoropyrimidines” are relative and subjective term which render the claim indefinite. The instant specification ( See page 6) provides a standard for ascertaining the requisite degree of high dose of B6 vitamer. However, "[f]or some facially subjective terms, the definiteness requirement is not satisfied by merely offering examples that satisfy the term within the specification." DDR Holdings, LLC v. Hotels.com, L.P., 773 F.3d 1245, 1261, 113 USPQ2d 1097, 1108 (Fed. Cir. 2014). MPEP 2173.05(b) IV. It’s not clear what “synergistic effect of fluoropyrimidines” is referring to: synergistic effect of fluoropyrimidines with the B6 vitamer , or synergistic effect of fluoropyrimidines with the folate, or synergistic effect of fluoropyrimidines, B6 vitamer and the folate. Different combination comprising different fluoropyrimidine species and B6 vitamer would have different plasma concentration. It’s not clear what plasma and/or intracellular levels of PLP is considered to enable synergistic effect of different fluoropyrimidine species. One of ordinary skill in the art would not know the metes and bound of the invention.
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 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 non-obviousness.
Claims 28, 29, 34-36 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Mortimer et al. (Cancer Chemotherapy and Pharmacology,1990, 26:449-452, “Weekly fluorouracil and high-dose leucovorin: efficacy and treatment of cutaneous toxicity”), in view of Machover et al. (Machover’2001 , Biochemical Pharmacology, 2001, Vol. 61, No. 7, pp. 867-876, Applicant’s IDS dated 09/20/2021, under “Non-Patent Literature Document”, Cite# 9, "Cytotoxic synergism of methioninase in combination with 5-fluorouracil and folinic acid ") and Matsubara et al. (Journal of Nutritional Biochemistry 2003,14, 246–250, "Vitamin B6-mediated suppression of colon tumorigenesis, cell proliferation, and angiogenesis”) .
Mortimer teaches pyridoxine (a B6 vitamer)(150mg daily) was administrated to patients (e.g. colorectal cancer, gastric cancer, etc.) undergoing cancer treatment with weekly administration of 5-Fluorouracil (FU, a fluoropyrimidine) and a high-dose of leucovorin (LV, a folate also known as folinic acid or 5- formyltetrahydrofolate), wherein the symptoms/complication of cutaneous toxicity were improved (page 449, Summary; page 451, right column, first paragraph; page 452, left column, second paragraph). 5-Fluorouracil (FU) is a fluoropyrimidine recited in instant claims 35, pyridoxine is a B6 vitamer recited in instant claims 35, leucovorin (LV) is a folate also known as folinic acid or 5- formyltetrahydrofolate that reads on instant claims 35. The subject undergoing cancer treatment is a subject afflicted with cancer which reads on instantly recited subject in need thereof under BRI,
Mortimer et al. teaches addition of high-dose leucovorin (LV) to 5-fluorouracil (FU) have increased the efficacy of FU, therefore combination therapy comprising 5-fluorouracil (FU) and leucovorin (LV) are effective for the treatment of progressive colorectal cancer (page 449, Summary, Introduction). Mortimer and incorporated reference (Ullman, etc.) teach folates in combination with FU
demonstrated in vitro cytotoxicity 5-fold that obtained with FU alone. Similar "potentiation" has been observed in animal models and in human colorectal cancer xenografts, and three randomized controlled trials in patients with advanced colorectal cancer wherein the addition of LV resulted in significantly higher response rates, suggesting a therapeutic efficacy as well (page 451, right column).
Mortimer teaches pyridoxine was administered to patients throughout their chemotherapy with FU and LV wherein patients continued to show tumor response while receiving the vitamin(See page 451, right column) (which reads on the limitation that drugs are administered simultaneously, separately or sequentially in instant claim 29). Mortimer suggested further understanding of the pathogenesis of this toxicity and of the role of pyridoxal phosphate in its resolution will enhance understanding of the cytotoxicity of FU ( See page 452, left column).
Regarding the additional anticancer agent recited in instant claim 34, Mortimer teaches patients with colorectal cancer and carcinoma of unknown primary sites (CUPS) received prior FU with or without cisplatin, patients with breast cancer had chemotherapy regimens including doxorubicin( See page 450, left column, last paragraph). Combination therapy is common practice in cancer treatment as taught by Mortier. It would have been obvious to one of ordinary skill in the art before the effective filing date of instant invention to further explore combination comprising 5-fluorouracil (FU), leucovorin(LV) and pyridoxine with one or more chemotherapeutic agent (e.g. cisplatin, doxorubicin) for cancer treatment.
Mortimer is silent about parental administration of high-dose of pyridoxine (B6 vitamer) and its effect on the cytotoxic activity of 5-fluorouracil. A skilled artisan would have known parenteral administration of B6 vitamer would result higher plasma concentration of PLP that might lead to better benefit/advantage than oral administration of B6 vitamer. It would have been obvious and logical for a skilled artisan to explore high-dose of pyridoxine (B6 vitamer) by parenteral administration for potential better benefit of reducing adverse event of 5-fluorouracil in cancer treatment.
As elaborated in preceding Claim Interpretation section, recitation of “increasing cytotoxic activity of fluoropyrimidine in a subject in need thereof” and wherein“ the cytotoxic activity of the fluoropyrimidine with the folate is enhanced by the parenteral administration of the B6 vitamer” in instant claims are construed as expression of intended function/result of administering a pharmaceutical combination /composition comprising fluoropyrimidine, B6 vitamer and folate, which do not necessarily or materially differentiate instant claimed method from prior art since such limitations do not result in manipulative difference in method steps of administering a pharmaceutical combination comprising fluoropyrimidine, folate and B6 vitamer based on the combined teachings of prior art and general knowledge of fluoropyrimidine, folate, B6 vitamer and cancer treatment. As stated in MPEP 2111.04: “the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Please also note biological/pharmaceutical activities are the properties of a pharmaceutical combination/composition comprising fluoropyrimidine, folate and B6 vitamer, and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances. “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir.1999).
Mortimer is silent about the mechanism of potentiation/ synergy between 5-fluorouracil and folinic acid. Machover’2001 teaches combination comprising 5-fluorouracil, folinic acid ((5-HCO-H4 folate) and methioninase for cancer treatment and potential mechanism that might contribute to the cytotoxic synergism thereof. Machover’2001 teaches potentiation of cytotoxic activity of 5-fluorouracil (FUra) by folinic acid (5-HCO-H4 folate) in colon tumors is due to elevation of the methylene tetrahydrofolate (CH2-R4 folate) level, which increases the stability of the ternary complex of thymidylate synthase (TS), fluorodeoxyuridine monophosphate (FdUMP), and CH2-H4 folate with concomitant inactivation of the TS (See Abstract). Machover’2001 teaches various concentration of 5-fluorouracil and folinic acid in cytotoxicity study, for example, FUra at 1 µM and 5 µM, 5-HCO-H4folate at 100 µM (See page 868, right column; Fig. 6).
Machover’2001 does not explicitly teach B6 vitamer administered in combination of 5-fluorouracil (FUra) and folinic acid. However, Machover’ 2001 teaches methioninase is associated with pyridoxal 5’-phosphate (PLP) in γ-elimination of methionine (See page 868 , left column), indicating pyridoxal 5’-phosphate (PLP)/ vitamin B6 plays an important role of in the synergic cytotoxic effect of methioninase with 5-fluorouracil and folinic acid. A skilled artisan would have known pyridoxal 5’-phosphate (PLP) is metabolite of pyridoxine in the combination therapy comprising 5-fluorouracil (FUra)/ folinic acid/ pyridoxine taught by Mortimer. Mortimer already suggested further exploration of the role of pyridoxal phosphate in understanding the cytotoxicity of FU. It would be obvious for a skilled artisan to further explore the role of B6 vitamer/ pyridoxal phosphate for the “potentiation” of cytotoxicity of FU in Mortimer’s combination therapy comprising B6 vitamer/ 5-fluorouracil (FUra)/ folinic acid based on the collective teachings of Machover’2001.
Matsubara teaches high levels of vitamin B6 suppress growth of some cancer cells(e.g. colon cancer), and have potential use in antineoplastic therapy (See abstract, Introduction on page 246). Matsubara and its incorporated references teach “high levels of vitamin B6 have been reported to suppress growth of animal or human cancer cells in vitro. Animal research also indicated that a high dietary intake of vitamin B6 suppresses herpes simplex virus type 2 transformed cell-induced tumor growth in BALB/c mice”(See introduction). Matsubara reviews studies on the antitumor effect of vitamin B6 and its potential mechanisms, for example, various amount of pyridoxine (PN) HCl reducing incidence of colon tumors (See page 247, left column, Figure 1) wherein vitamin B6 reduced the BrdU-labeling index of cell proliferation in the colon of mice. Matsubara teaches pyridoxal 5’-phosphate (PLP) is an effective inhibitor of many enzymes that have binding sites for phosphate-containing substrates or effectors, including RNA polymerase, reverse transcriptase, DNA polymerase, etc. that might be associated with inhibitory effect of vitamin B6 on colon cell proliferation (See page 247, right column). Matsubara teaches antiangiogenic effect of pyridoxal 5’-phosphate (PLP) and pyridoxine (PN) (See page 248, right column, Figure 3.) and inhibition of angiogenesis induced by tumor and metastasis cells is a promising therapeutic strategy for cancer. Matsubara also teaches other potential mechanism that might lead to the antitumor effect of vitamin B6, such as roles in homocysteine catabolism, transfer of methyl group to tetrahydrofolate yielding 5, 10-methylenetetrahydrofolate for reactions generating thymidylate and purines, etc.(See page 249, left column). As elaborated, Matsubara collectively teaches vitamin B6 (e.g. PLP, pyridoxine) at higher dose as potential antitumor agent in antineoplastic therapy. Regarding the limitation of plasma and/or intracellular levels of PLP for optimum synergistic effect of the fluoropyrimidines recited in instant claim 41, the plasma and/or intracellular level of PLP is the property/direct result of B6 vitamer once the B6 vitamer is metabolized within the organism. Matsubara teaches various doses of B6 vitamer (PN and LP). 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. MPEP 2144.05.
It would have been obvious to one of ordinary skill in the art before the effective filing date of instant claimed invention to further explore the combination therapy comprising 5-fluorouracil/ folinic acid/ pyridoxine taught by Mortimer based on combined teachings of Mortimer, Machover’2001 and Matsubara, together with exploration/optimization (e.g. administration route, dose, etc.) based on general knowledge of fluoropyrimidine, B6 vitamer, folate and cancer treatment, and arrive at the instantly claimed invention with reasonable expectation of success. Before the effective filing date of instant claimed invention, it was already known combination therapy comprising 5-fluorouracil/ folinic acid/ pyridoxine was used in cancer treatment as taught by Mortimer. It was also known that combination therapy comprising 5-fluorouracil and folinic acid have synergistic effect and mechanism thereof as taught by Machover’2001. It was also known that vitamin B6 might be an antitumor agent with different mechanism in antineoplastic therapy as taught by Matsubara.
A person of ordinary skill in the art would be motivated to further explore the potential synergistic effect of Mortimer’s combination therapy comprising 5-fluorouracil/ folinic acid/ pyridoxine based on combined teachings of Mortimer , Machover’2001 and Matsubara, because Mortimer suggested further exploration of the role of pyridoxal phosphate in understanding the cytotoxicity of FU, Machover’ 2001 teaches methioninase is associated with pyridoxal 5’-phosphate (PLP) in γ-elimination of methionine indicating pyridoxal 5’-phosphate (PLP)/ vitamin B6 plays an important role of in the synergic cytotoxic effect of methioninase with 5-fluorouracil and folinic acid. A skilled artisan would have known pyridoxal 5’-phosphate (PLP) is metabolite of pyridoxine in the combination therapy comprising 5-fluorouracil (FUra)/ folinic acid/ pyridoxine taught by Mortimer. Matsubara also elaborates the mechanism of B6 vitamer in cancer treatment. The further exploration /study of the Mortimer’s combination therapy comprising 5-fluorouracil/ folinic acid/ pyridoxine would provide more insight about role of B6 vitamer/ pyridoxal 5’-phosphate (PLP) on the cytotoxicity of FU. A person of ordinary skill in the art would know to measure the PLP level of different doses of B6 vitamer through experimentation/optimization based on the general knowledge of B6 vitamer, 5-fluorouracil and cancer treatment to achieve optimum cytotoxic effect of fluoropyrimidines for cancer treatment.
Please note biological/pharmaceutical activities are properties of a pharmaceutical combination/composition comprising fluoropyrimidine, folate and B6 vitamer and the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances. If combination of prior art teach a method of administering combination of fluoropyrimidine, folate and oral administration of B6 vitamer to a subject afflicted with cancer exhibiting benefit/advantage (e.g. less adverse event) in cancer treatment, a skilled artisan would have known parenteral administration of B6 vitamer resulting higher plasma concentration of PLP would provide better benefit/advantage than oral administration of B6 vitamer, " increasing cytotoxic activity of fluoropyrimidine in a subject " will naturally flow from the combined teachings of prior art together with general knowledge of cancer treatment, since the composition/combination (fluoropyrimidine, folate and B6 vitamer ) is being administered to the same subjects (subject afflicted with cancer). In other words, even though the prior art is silent about " increasing cytotoxic activity of fluoropyrimidine in a subject ", by practicing the method of administering combination of fluoropyrimidine, folate and B6 vitamer to a subject afflicted with cancer made obvious by combination of prior art, together with general knowledge of parenteral administration providing higher plasma concentration of PLP and cancer treatment, one would also be " increasing cytotoxic activity of fluoropyrimidine in a subject afflicted with cancer ", even though the prior art was not aware of it.
One of ordinary skill in the art would have had reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art, together with exploration /optimization base on general knowledge of B6 vitamer, folate and fluoropyrimidine in cancer treatment.. 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, as evidenced by the references, especially in the absence of evidence to the contrary. Applicant might have discovered a new property or advantage/mechanism of "increasing cytotoxic activity of fluoropyrimidine in a subject by parenteral administration of B6 vitamer" for the method of "administering combination of fluoropyrimidine, folate and B6 vitamer to a subject afflicted with cancer” made obvious by the prior art together with general knowledge of cancer treatment. MPEP 2145 II states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
Response to Arguments
Applicant's arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
MORTIMER:
Applicant argues pyridoxine was not administered to all patients (only in a minority of them) and Mortimer did not administer pyridoxine parenterally or even consider using this route... A person skilled in the art would therefore have had no apparent reason to use pyridoxine in combination with FU/LV to improve the efficacy of cancer treatment by using much higher doses of pyridoxine from the start of chemotherapy and administering said doses parenterally (Remarks, page 17-19).
RESPONSE: Applicant’s argument is fully considered, but NOT persuasive. The fact that pyridoxine was administered to a subset of patient for different function/ benefit in cancer treatment does not detract/negate the clear teaching of co-administration of pyridoxine with FU/LV therapy taught by Mortimer.
As elaborated in Claim Interpretation section and above 103 rejection, recitation of “increasing cytotoxic activity of fluoropyrimidine in a subject in need thereof” and wherein“ the cytotoxic activity of the fluoropyrimidine with the folate is enhanced by the parenteral administration of the B6 vitamer” in instant claims are construed as expression of intended function/result of administering a pharmaceutical combination/composition comprising fluoropyrimidine, B6 vitamer and folate, which do not necessarily materially differentiate instant claimed method from prior arts since such limitations do not result in manipulative difference in method steps of administering a pharmaceutical combination comprising fluoropyrimidine, folate and B6 vitamer based on the combined teachings of prior art and general knowledge of fluoropyrimidine, folate, B6 vitamer and cancer treatment. As stated in MPEP 2111.04: “the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Please note biological/pharmaceutical activities are the properties of a pharmaceutical combination/composition comprising fluoropyrimidine, folate and B6 vitamer, the products of identical or similar composition cannot exert mutually exclusive properties when administered under the same or similar circumstances. If combination of prior art teach a method of administering combination of fluoropyrimidine, folate and oral administration of B6 vitamer to a subject afflicted with cancer exhibiting benefit/advantage (e.g. less adverse event) in cancer treatment, a skilled artisan would have known parenteral administration of B6 vitamer resulting higher plasma concentration of PLP would provide better benefit/advantage than oral administration of B6 vitamer. Even though the prior art is silent about " increasing cytotoxic activity of fluoropyrimidine in a subject ", by practicing the method of administering combination of fluoropyrimidine, folate and B6 vitamer to a subject afflicted with cancer made obvious by combination of prior art, together with general knowledge of parenteral administration providing higher plasma concentration of PLP and cancer treatment, one would also be " increasing cytotoxic activity of fluoropyrimidine in a subject afflicted with cancer ", even though the prior art was not aware of it.
MACHOVER’ 2001
Applicant argues Machover’ 2001 only states that methioninase is active in the presence of PLP... Nowhere in Machover is it indicated that PLP is administered to the patients(Remarks, page 19-20).
RESPONSE: It’s noted instant specification disclosed the plasma concentration of PLP as in combination with FUra-FA. Although Machover’ 2001 is silent about addition of PLP with the combination of 5-FU and folinic acid. Machover’ 2001 teaches methioninase is associated with pyridoxal 5’-phosphate (PLP) in γ-elimination of methionine, indicating pyridoxal 5’-phosphate (PLP)/ vitamin B6 plays an important role of in the synergic cytotoxic effect of methioninase with 5-fluorouracil and folinic acid. A skilled artisan would have known pyridoxal 5’-phosphate (PLP) is metabolite of pyridoxine in the combination therapy comprising 5-fluorouracil (FUra)/ folinic acid/ pyridoxine taught by Mortimer. Mortimer already suggested further exploration of the role of pyridoxal phosphate in understanding the cytotoxicity of FU. A skilled artisan would be motivated to further explore the role of B6 vitamer/ pyridoxal phosphate for “potentiation” of cytotoxicity of FU in Mortimer combination therapy comprising B6 vitamer/ 5-fluorouracil (FUra)/ folinic acid based on the combined teaching of Machover’ 2001.
MATSUBARA:
Applicant argues Matsubara is essentially concerned with the preventive effect of dietary vitamin B6 against colon tumorigenesis and its possible mechanisms" and “Nowhere in Matsubara is there any hint to the fact that vitamin B6 could be used treat colon cancer let alone in combination with fluoropyrimidine and a folate... neither K. Matsubara nor S. Komatsu ever considered the curative aspect of vitamin B6 (Remarks, page 21).
RESPONSE: Matsubara reviews studies on the antitumor effect of vitamin B6 and its potential mechanisms and teaches various amount of high dose pyridoxine (PN) HCl reducing incidence of colon tumors wherein vitamin B6 reduced the BrdU-labeling index of cell proliferation in the colon of mice. Matsubara also teaches pyridoxal 5’-phosphate (PLP) is an effective inhibitor of many enzymes that have binding sites for phosphate-containing substrates or effectors, including RNA polymerase, reverse transcriptase, DNA polymerase, etc. that might be associated with inhibitory effect of vitamin B6 on colon cell proliferation. Matsubara’s teaching might provide further insight of possible mechanism regarding the role/ of B6 vitamer in the combination comprising fluoropyrimidine and B6 vitamer. A skilled artisan would be motivated to further explore vitamin B6 (e.g. PLP, pyridoxine) at higher dose as potential antitumor agent in antineoplastic therapy.
Applicant argues against cited reference (Littman, Vrolijk (2017) and further cites reference about serine hydroxymethyltransferase (SHMT) associated with vitamin 6 in cancer treatment as the prejudice that addition of vitamin B6 to the combination would lead to a reduction in the efficacy of FU/LV combination (Remarks, pages 24-30). Applicant concludes “the addition of vitamin B6 to an anti-cancer combination is counterintuitive and that the skilled person had to overcome an established prejudice in order to test the three-product combination... it was not obvious to test the addition of B6 to the Combination with a reasonable expectation of success”(Remarks, page 30).
RESPONSE: Applicant’s argument is considered, but NOT persuasive. The “prejudice” based on serine hydroxymethyltransferase (SHMT) associated with vitamin B6 against addition of vitamin B6 to anti-cancer combination is only one aspect of cancer treatment which is high unpredictable due to vast variety of enzyme target with different mechanism. A skilled artisan would not be discouraged by the uncertainties of pyridoxine in cancer treatment . Instead, a skilled artisan might have been motivated to further explore the role/mechanism of pyridoxine and its interaction with 5-FU in cancer treatment that might lead to optimum combination comprising 5-FU/ pyridoxine/folinic acid.
Under BRI, a method of treating cancer is not limited to improving the efficacy of active drug/ingredients, but also refer to method of reducing side-effects of anticancer drug, improving pharmacokinetic profile and safety profile of active ingredients in treating cancer, etc. 5-fluorouracil is a well-known chemotherapy agent with sever side-effects and skilled artisan have been trying to reduce 5-FU’s side-effect with leucovorin, in combination with vitamin B6 as taught by prior art. Mortimer might not know the beneficial effect of pyridoxine on the efficacy of the said FU+LV conventional treatment, a skilled artisan would have known that more patients would have continued 5-FU treatment by administrating pyridoxine and reducing the side-effect of 5-FU which would translate into overall efficacy of 5-FU treating cancer. A skilled artisan would have also known parenteral administration of B6 vitamer would result higher plasma concentration of PLP that might lead to better benefit/advantage than oral administration of B6 vitamer. It would have been obvious and logical for a skilled artisan to explore high-dose of pyridoxine (B6 vitamer) by parenteral administration for potential better benefit of reducing adverse event of 5-fluorouracil in cancer treatment.
Applicant might have discovered a new property or advantage/mechanism of "increasing cytotoxic activity of fluoropyrimidine in a subject by parenteral administration of B6 vitamer" for the method of "administering combination of fluoropyrimidine, folate and B6 vitamer to a subject afflicted with cancer” made obvious by the prior art together with general knowledge of cancer treatment. MPEP 2145 II states: "The fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art, cannot be the basis for patentability when the differences would otherwise be obvious". Ex parte Obiaya, 227 USPQ 58, 60. (FP 7.37.07, MPEP 707.07(f)).
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.
Claims 28, 29, 34-36 and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14-25 of copending Application No. 18/702,490 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claims are directed to a method of treating various cancers in a subject, comprising administering to a subject in need thereof an antitumor pharmaceutical composition comprising (i) a fluoropyrimidine, (ii) a B6 vitamer, and (iii) a folate. Reference claims 16-19 and 21 recite fluoropyrimidine, B6 vitamer and folate that read on instant fluoropyrimidine B6 vitamer and folate. Reference claim 20 recites limitation wherein the B6 vitamer is administered at a dose high enough to achieve plasma or intracellular levels of PLP equal to or greater than those required for optimal synergistic effect of fluoropyrimidines (which reads on instant claims 28, and 41). Reference claims recite cancer type which is narrower scope than instant claims, thus anticipate instant claimed invention.
The instant application shares one common inventor with the reference application. Based on the continuing data on the record, instant application is not related to the reference application, thus no 35 USC 121 shield exists.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
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/L.M./Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628