DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-10 are pending and under consideration in this action.
Abbreviations Used Herein
5-MFA – 5-methyltetrahydrofolic acid
PHA – phytohemagglutinin
Claim Objections
Claim 1, line 8 recites a limitation of ‘affect the function of iNOS expression to produce a safe amount’. It is noted that ‘and’ is missing between ‘iNOS expression’ and ‘to produce a’. Appropriate correction is required.
Claim 8 refers to a method of “using a composition as in claim 1”. Claim should read “using a composition of claim 1”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-10 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.
The term “substantially” in claim 1 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
The term “a safe amount” in claims 1 and 8 is a relative term which renders the claim indefinite. The term “a safe amount” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 1 recites a limitation of ‘the compound comprising an amount of NO toxicity’. Specifically, the phrase "comprising" renders the products indefinite as the phrase It is noted that "comprising" can be considered open-ended language when not clearly defined and therefore is including additional subject matter. A chemical compound cannot be open-ended, but must be claimed with precision. In other words, the compound is a single agent and cannot comprise an amount of NO toxicity decreasing agent. The compound is NO toxicity decreasing agent, 5-methyltetrahydrofolic acid. It is suggested that the claim be amended to read on, A composition comprising an ‘NO decreasing agent, 5-methyltetrahydrofolic acid, an NO extender etc. Also in claim 1, it is not clear whether the NO extender comprises an amino acid or the NO extender is an amino acid (e.g. arginine). According to the specification, NO extender is selected from enzyme producing NO substrates, NO substrates selected from L-arginine or salt thereof, citrulline or salt thereof, or arginine activator additive (See [0037]). Appropriate correction is required.
Claims 2-3, 5 recite limitations of ‘wherein the NO extender is an amount of arginine’, ‘wherein the nitric oxide synthase inducer is an amount of phytohemagglutinin’, ‘wherein the NO extender is an amount of arginine and the nitric oxide synthase inducer is an amount of phytohemagglutinin’ respectively. The agent cannot be an amount of agent. For e.g. NO extender is arginine but not an amount of arginine. It is suggested that the claims be amended to reflect the agents. Appropriate correction is required.
Claims 4, 6-7, and 9-10 have been rejected for depending upon the limitations of claim 1.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Rabelink et al. (US 6,995,158 B2 – previously cited); in view of Kesherwani et al. (Nitic Oxide, 16, 2007, 294-305 – previously cited).
Regarding claims 1-5, Rabelink discloses a composition comprising the NO toxicity decreasing agent 5-methyltetrahydrofolic (5-MFA) acid and the NO extender arginine (an amino acid) (Example 10, col. 14, lines 15-30).
Rabelink does not teach the 5-MFA and arginine composition further comprising a NOS inducer, like phytohemagglutinin (PHA) (claims 1-5). The teachings of Kesherwani et al. are relied upon for these disclosures.
Kesherwani teaches that PHA induces L-arginine mediated NO production in macrophages (page 301, col. 2, para. 1, last line) and that PHA induces activation of macrophages in vitro (page 301, para. 2). The results indicate enhanced transcription of iNOS gene and iNOS protein in PHA treated macrophages (page 301, col. 2, para. 2). Thus, the administration of PHA allows for enhanced regulation of NO levels in cells as a result of increased macrophage activation, suggesting improvement of an immunological response.
Regarding inclusion of PHA into the 5-MFA and arginine formulation, as recited in claims 1-5, it would have been prima facia obvious to one of ordinary skill prior to the effective filing date of the claimed invention to combine the teachings of Rabelink and Kesherwani to arrive at a pharmaceutical composition that allows for enhanced regulation of NO levels in cells. One of ordinary skill would have been motivated to combine these teachings because enhanced regulation of NO levels in cells, as disclosed by Rabelink, leads to more effective prevention and treatment of cardiovascular and neurological disorder (Col. 1, para. 2, lines 24-29). One of ordinary skill would have had a reasonable expectation of success in doing so, as the combined teachings of Rabelink and Kesherwani point to a formulation with enhanced regulation of NO levels in a subject comprising 5-MFA, arginine and PHA.
Applicant is advised, it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose (See MPEP 2144.06-I, In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)).
Regarding the claimed ranges in instant claims 4, 7, and 9, Rabelink discloses administration of a composition comprising 25 mg of 5-MFA and 250 mg of arginine (1: 10 mass ratio, reading on instant 2: 8 for 5-MFA and arginine) (Example 10, col. 14, lines 15-30). Kesherwani discloses in vitro administration of 1-2 µg/ mL (page 301, col. 2, para. 2; and Table 1, page 296) – all reading on the instant claims of 30 or 50 mg/kg administration of the claimed composition.
Applicant is advised that the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See 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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that 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. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Regarding claim 6, the instant specification discloses the composition of 5-MFA and arginine can significantly increase the level of T cells in a virus infected host (page 9, [0039] and [0041]). Rabelink does not disclose any components that would preclude administration of their composition to a subject infected by a viral infection. In fact, Rabelink’s invention is intended for administration to subjects with the goal of modulating NOS activity (abstract). Therefore, Rebelink’s and Kesherwani’s composition is capable of performing the claimed intended use.
Regarding claim 8, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the instant application to administer a combination of Rabelink’s 5-MFA and arginine composition further comprising Kesherwani’s PHA to induce production of a safe amount of NO in a subject. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Rabelink discloses their 5-MFA and arginine composition for modulation NOS and producing NO in a subject; and Kesherwani suggests that administration of PHA with arginine allows for enhanced regulation of NO levels in cells as a result of increased macrophage activation, suggesting improvement of an immunological response.
Regarding claim 10, the instant claims are drawn to 5-MFA only as the NO toxicity decreasing agent. Rabelink discloses their 5-MFA and arginine composition is intended for administration to subjects with the goal of modulating NOS activity (abstract). Therefore, since the claimed component is the same as that disclosed by the cited art, then it must be capable of performing the cited use, i.e. not inhibiting expression of iNOS.
Regarding the claimed range of no less that 10 µmol/ L, Rabelink teaches their composition comprising 25 mg of 5-MFA (Example 10, col. 14, lines 15-30). Thus, Applicant is reminded the courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. The courts have also found that 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.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
Response to Arguments
Claims
Claim amendments are acknowledged. Amendments in response to claim interpretations submitted in non-final action filed April 15th, 2025 are acknowledged. No new matter has been introduced.
Objections to Drawings
Applicant’s arguments, see page 4, filed October 15th, 2025, with respect to objection of the drawings have been fully considered and are persuasive. The objection of the drawings has been withdrawn.
Claim Objections
Applicant’s arguments, see page 4, filed October 15th, 2025, with respect to objection of claim 1 have been fully considered and are persuasive. The objection of claim 1 has been withdrawn.
Claim Rejections - 35 USC § 112(a)
Applicant’s arguments, see pages 4-5, filed October 15th, 2025, with respect to 35 USC § 112(a) rejections have been fully considered and are persuasive. The 35 USC § 112(a) rejections have been withdrawn.
Claim Rejections - 35 USC § 112(b)
Applicant’s arguments, see pages 4-5, filed October 15th, 2025, with respect to 35 USC § 112(b) rejections have been fully considered and are persuasive. The 35 USC § 112(b) rejections have been withdrawn. However, upon further consideration, a new ground of 35 USC § 112(b) rejections have been made in view of claim amendments.
Claim Rejections - 35 USC § 102
Applicant’s arguments, see pages 5-6, filed October 15th, 2025, with respect to 35 USC § 102 rejections have been fully considered and are persuasive. The 35 USC § 102 rejections have been withdrawn.
Claim Rejections - 35 USC § 103
Applicant’s arguments with respect to claims 1-9 have been considered but are moot because the new ground of rejection does not rely on Wang, Schulz, or Seals, as applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Applicant argues the teachings of Rabelink do not include the claimed compositions and that the claimed composition would not have been obvious based on Rabelink combined with the cited art, and that Kesherwani doesn’t alleviate the deficiencies in Rabelink because Kesherwani references phytohemagglutinin (PHA) in the context of activation of murine peritoneal macrophages, not to the composition as instantly claimed. Applicant states that a person of ordinary skill would not be led to Kesherwani in relation to the teachings of Rabelink for any reason.
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). One of ordinary skill in the art would have found it obvious to arrive at the claimed composition for the reasons stated in the rejection above.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Rabelink discloses a composition comprising the NO toxicity decreasing agent 5-methyltetrahydrofolic (5-MFA) acid and the NO extender arginine to modulate NO production in a subject. Kesherwani relates to compositions comprising PHA for regulation of NO and teaches that PHA induces L-arginine mediated NO production in macrophages. Thus, one of ordinary skill would have been motivated to combine, and had a reasonable expectation of success in doing so, to arrive at the instant invention.
In response to applicant's argument that the cited art relates to the instantly claimed components in a context that differs from the instantly claimed intended use, a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
In the present case, Rabelink discloses 5-MFA and arginine as part of a composition for modulation NOS and NO production in a subject. Kesherwani discloses that PHA induces L-arginine mediated NO production in macrophages, and reports enhanced transcription of iNOS gene and iNOS protein in PHA treated macrophages. Applicant is reminded, as stated in the rejection above, that it is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.
Therefore, the instant claims stand rejected over Rabelink in view of Kesherwani, as set forth above.
Double Patenting
Applicant’s arguments, see page 9, filed October 15th, 2025, with respect to obviousness-type non-statutory double patenting rejections have been fully considered and are persuasive. In light of Application No. 17/632,003 being abandoned, the NSDP rejection has been withdrawn.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/Umamaheswari Ramachandran/Primary Examiner, Art Unit 1627