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 .
Claim Objections
Claims 1, 2 and 6 are objected to because of the following informalities: please italicize the species names. 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.
Claim 3 is 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.
Claim 3 is indefinite because it is unclear what method the claim is trying to describe. Although it is clear that the claim is drawn to a method of synthesizing β-nicotinamide mononucleotide, the only method step is that of “using” the claimed composition, there are no steps on how the compositions is supposed to be applied, and any other nature on the procedure for synthesizing the claimed compound. Since there is a named utility for the claimed method, the claim should be eligible under 35 USC 101, but since it is unclear how the method is performed, the claim is considered indefinite. See MPEP 2172.01. For the sake of examining the claim on its merit, it will be assumed that the method of claim 3 is the similar to the method in claim 4.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1 and 2 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The claim(s) recite(s) a two-enzyme composition. This judicial exception is not integrated into a practical application because the claims are drawn to a two-enzyme composition, wherein each enzyme behaves as it would in nature. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims only recite the products of nature. For the analysis of the claims under 35 USC 101, the Applicant is directed to MPEP 2106, especially the flow chart provided in subsection III.
The claims are drawn to a composition, and as such, they define a statutory category, and pass step 1 of the flow chart. Since the claims comprise two naturally occurring enzymes, the claims must be analyzed as being considered a product of nature (step 2A). The claims provide for a two-enzyme system comprising nicotinamide riboside kinase and purine nucleotide phosphorylase, wherein it is clear from the instant specification and the prior art that these enzymes are naturally occurring and have not been engineered in any manner. As such, individually, these enzymes must be considered nature-based products (see MPEP 2106.04(b)); however, since the enzymes are provided in a two-enzyme system, the system as a whole must be considered. When considering this, the Applicant is directed to the “Markedly Different Characteristics Analysis.” See MPEP 2106.04(c). When looking at the behavior of each enzyme, individually, then considering the two-enzyme system, as a whole, it appears as though each enzyme performs its catalytic action as they would individually. That is to say, each enzyme’s kinetics and substrate/product behaviors are the same, regardless of the presence or absence of the other claimed enzyme. See Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130, 76 USPQ 280, 281 (1948).
Based upon the “Funk Bros.” guidance, even though the two enzymes are isolated from different species, they both behave as they would in isolation, and thusly, the composition fails the markedly different characteristics analysis. Since the claims do not recite anything more than the nature-based product, and do not provide for a composition that possesses markedly different characteristics compared to the natural counterparts, the claims are not eligible under 35 USC 101.
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 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Marinescu, et al (Scientific Reports, 8, 12278, 2018) and evidenced by Gossman, et al (The FEBS Journal, 279, 3355-3363, 2012) and Lawrence, et al (US Pat. 10,913,965). Marinescu teaches methods of producing β-nicotinamide mononucleotide (NMN) by engineering Escherichia coli to express certain enzymes. See page 1, “Abstract” section. Marinescu provides for nicotinamide phosphoribosyl transferase (Nampt; EC 2.4.2.12) and phosphoribosyl pyrophosphate synthetase (PRPP synthetase; EC 2.7.6.1). See page 1, “Introduction” section, 2nd paragraph; page 7, 4th [full] paragraph. Nampt is functionally almost identical to the claimed purine nucleoside phosphorylase (PNP) (based upon similar enzyme commission numbers, wherein EC 2.4.2.1 defines purine-nucleoside phosphorylases), whereas PRPP synthetase is functionally similar, yet different than the claimed nicotinamide riboside kinase (NRK) (wherein EC 2.7 describe enzymes that transfer phosphorus containing groups). As such, even though Marinescu teaches different enzymes, the described enzymes provide for almost identical, or at least similar functionality. It should also be noted, if an enzyme is described with an EC number, its function can be described as predictable.
Gossman describes the biosynthetic pathway for the generation of NAD+, wherein the claimed PNP and NRK are shown in the biosynthetic pathway. See page 3357, Figure 1. This reaction scheme shows that the ordinary artisan knows what substrates each enzyme catalyzes, and what products form in these reactions. Knowledge of the full reaction scheme shows that the ordinary artisan would expect a high level of predictability when applying these enzymes individually. The graphic shows that there is a reasonable expectation that NRK will catalyze the phosphorylation of nicotinamide riboside (NR) to NMN, with ATP as a reactant. The graphic also shows that PNP will catalyze the reaction of NR to nicotinamide (NAM). Although it should be noted, although Gossman does not state that the PNP reaction is reversible, Lawrence explicitly describes this enzymatic reaction as a reversible reaction. See column 2, lines 27-57.
Based upon the engineered E. coli of Marinescu that is engineered with enzymes that are the same, or similar to those claimed, and the highly predictable nature of the NAD+ biosynthetic pathway, would suggest that the manufacture of NMN with the claimed enzyme system would be obvious to the ordinary artisan. When considering the claims, in the context of the cited prior art, it appears as though the claimed composition and method are obvious variants of Marinescu’s method and system, wherein similar or obvious variants to the enzymes of Marinescu are substituted out to make the claimed system. Knowledge of this enzymatic pathway would make these substitutions predictable to the ordinary artisan.
With respect to claims 1, and 3, Marinescu teaches an obvious variant of the claimed enzyme-system, wherein the substitution of one of Marinescu’s enzymes would lead to a predictable outcome. That is to say, Gossman and Lawrence make it obvious to the ordinary artisan that the substitution of PRPP synthetase with NRK would predictably continue to yield NMN. Additionally, Lawrence notes that PNP can be isolated from E. coli and Bacillus subtilis. See column 2, lines 34 and 35.
With respect to claim 2, Gossman indicates that NRK can be isolated from Homo sapiens. See page 3358, Table 1.
With respect to claim 4, Marinescu begins with nicotinamide, and as such, this would be an obvious starting compound. Gossman shows NRK will catalyze the phosphorylation of NR to NMN, with ATP as a reactant. This would inform the ordinary artisan that ATP must be present for the reaction to occur. Also, based upon Gossman and Lawrence (who notes the reversibility of the PNP reaction), it would be obvious to include adenosine, because this is how the nicotinamide acquires the ribose unit. Finally, Marinescu utilizes Luria-Burtani broth, which includes both magnesium and phosphate, in the form of magnesium phosphate. See page 8, “Bacterial growth conditions” section. As such, the prior art either directly instructs the ordinary artisan, or provides ample motivation to the ordinary artisan to apply all of the claimed compounds in a method for making NMN.
With respect to claims 5 and 6, Marinescu teaches providing the enzymes, recombinantly, into E. coli in a method for making NMN.
With respect to claim 7, although the cited prior art provides for engineered E. coli, the fact that the enzymatic reaction is exceptionally predictable would suggest that there would be reasonable expectation that a solution of the isolated enzymes would predictably catalyze the reaction in a manner that would be expected to produce NMN. This would be obvious based on the known behavior of the claimed enzymes, and the fact that enzymatic behavior can be quite predictable.
With respect to claim 8, it is clear from the cited prior that the claimed NMN is a value-product. See Marinescu, page 1. As such, although the cited prior art does not teach the claimed isolation methods, there is a strong implicit motivation to isolate and purify NMN. Therefore, any well-known method of isolating this compound would be obvious to use. The claimed method is a generic method of filtering, chromatographic separation, and crystallization. This methodology is highly routine, and would be obvious to the ordinary artisan.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID W BERKE-SCHLESSEL whose telephone number is (571)270-3643. The examiner can normally be reached M-F 8AM-5:30PM.
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/DAVID W BERKE-SCHLESSEL/ Primary Examiner, Art Unit 1651