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
Amendments
In the reply filed on 08/03/2026, Applicant has amended claims 3, 5 and 6, and has added new claims 13-16.
Election/Restriction
Applicant’s election, without traverse, of Group I, claims 1-5 and 13-16, drawn to a method for maintaining or improving platelets, in the reply filed on 08/03/2026 is acknowledged.
Claims 6-8 and 11-12 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Status
Claims 1-8 and 11-16 are pending.
Claims 6-8 and 11-12 are withdrawn.
Claims 1-5 and 13-16 are considered on the merits.
Priority
This application is a 371 of PCT/CN2022/131812 (filed on 11/15/2022), which claims benefit from foreign application CN202111346275.7 (filed on 11/15/2021). The priority claim of the instant application has been granted and the earliest benefit date is 11/15/2021 from the application CN202111346275.7.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 05/15/2024 and 08/16/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner. The corresponding signed and initialed PTO forms 1449 have been mailed with this action.
Objection to Drawings
Sequence Compliance
Figure 5E (amino acid sequences of CPT2 molecules in various organisms) of the Specification does not conform to sequence rules, requiring the use of “SEQ ID NO:” for each amino acid sequence showin in Fig 5E (37 CFR 1.821-1.825).
Where the description or claims of a patent application discuss a sequence that is set forth in the “Sequence Listing” in accordance with paragraph (c) of this section, reference must be made to the sequence by use of the sequence identifier, preceded by “SEQ ID NO:” in the text of the description or claims, even if the sequence is also embedded in the text of the description/figures or claims of the patent application. 37 CFR 1.821 (d).
The applicant is reminded that the specification must be amended in order to comply with regulations cited above. All references to sequences in claims and specification should be referred to as “SEQ ID NO:1”, for example. To avoid all doubts of the examiner and to ensure correct interpretation of the claims and specification, the identification of sequences with proper sequence identifiers is required.
Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
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 1-3 and 13-14 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.
Claim 1 recites the limitation “the objects in need” in the last line. There is insufficient antecedent basis for this limitation in the claim because the term “objects” has not been recited prior to this limitation. Since the only objects recited in claim 1 is platelets, “the objects in need” is examined as “the platelets”. Claims 2-3 and 13-14 are rejected as being dependent from claim 1 but not resolving the ambiguity.
Additionally, claim 1 recites a method for maintaining or improving the activity of platelets, …, comprising using CPT2 or an up-regulator thereof to the objects in need (i.e., to the platelets. Underlined by examiner). In other words, claim 1 recites a method for using CPT2 or its up-regulator to maintain or improve platelet activity. MPEP 2173.05(q) states “Attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. For example, a claim which read: “[a] process for using monoclonal antibodies of claim 4 to isolate and purify human fibroblast interferon” was held to be indefinite because it merely recites a use without any active, positive steps delimiting how this use is actually practiced. Ex parteErlich, 3 USPQ2d 1011 (Bd. Pat. App. & Inter. 1986). In the instant case, the claim merely recites a method for using CPT2 or up-regulator to the platelets to maintain or improve platelet activity, without any active, positive steps delimiting how this use is actually practiced, thus is indefinite.
Claim Rejections - 35 USC § 112(a)
(Written Description)
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-5 and 13-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Specifically, independent claims 1 and 4, and their dependent claims encompass a genus of method for maintaining or improving the activity, quality, survival, lifespan or counts of platelets (stored in vitro in claim 4) comprising using or treating with CPT2 or a genus of up-regulator thereof, in any concentration, to the platelets. The genus of up-regulator of CPT2 comprises e.g., any protein acetylation inhibitors, any antioxidants, any expression construct for recombinantly expressing CPT2, any up-regulator that promotes the driving ability of CPT2 gene promoter, or any down-regulator of CPT2 gene-specific microRNA (see e.g. claim 3 and claim 5).
However, the specification only discloses a genus of method with a limited number of species for maintaining or improving the activity, quality, survival, lifespan or counts of platelets comprising treating the platelets in vitro with a tip60 inhibitor, a p300 inhibitor (Example 5, p.29), NMN, NR, P7C3, SBI-797812 (Example 5, p. 30-31), a specific AMPK inhibitor Dorsomorphin (Example 6, p. 33), N-acetylcysteine, Mesna, Glutathione (Example 7, p. 34), or a combination of NMN+NAC+Dorsomorphin (Examples 8-10, p. 34-35), each in specified concentration.
Under the written description guidelines (see MPEP 2163) the Examiner is directed to determine whether one skilled in the art would recognize that the Applicant was in possession of the claimed invention as a whole at the time of filing. The following considerations are critical to this determination.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. An original claim may lack written description support when (1) the claim defines the invention in functional language specifying a desired result but the disclosure fails to sufficiently identify how the function is performed or the result is achieved or (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). The written description requirement is not necessarily met when the claim language appears in ipsis verbis in the specification. "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement." Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002).
Accordingly, to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of method for maintaining or improving the activity, quality, survival, lifespan or counts of platelets comprising using or treating with CPT2 or a genus of up-regulator, in any concentration, that comprises e.g., any protein acetylation inhibitors, any antioxidants, any expression construct for recombinantly expressing CPT2, any up-regulator that promotes the driving ability of CPT2 gene promoter, or any down-regulator of CPT2 gene-specific microRNA (see e.g. claim 3 and claim 5). However, the specification only discloses and provides guidance for a limited number of species of the method comprising treating the platelets in vitro with 10 specific individual compounds and one specific combination, including a tip60 inhibitor, a p300 inhibitor (Example 5, p.29), NMN, NR, P7C3, SBI-797812 (Example 5, p. 30-31), a specific AMPK inhibitor Dorsomorphin (Example 6, p. 33), N-acetylcysteine, Mesna, Glutathione (Example 7, p. 34), or a combination of NMN+NAC+Dorsomorphin (Examples 8-10, p. 34-35), each in specified concentration. Thus, the specification fails to describe the genus of methods.
ACTUAL REDUCTION TO PRACTICE
Accordingly, Applicant did not demonstrate a reduction to practice of a genus of method for maintaining or improving the activity, quality, survival, lifespan or counts of platelets comprising using or treating with CPT2 or a broad genus of up-regulator that comprises e.g., any protein acetylation inhibitors, any antioxidants, any expression construct for recombinantly expressing CPT2, any up-regulator that promotes the driving ability of CPT2 gene promoter, or any down-regulator of CPT2 gene-specific microRNA, nor did Applicant adequately set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of method for maintaining or improving platelets using the claimed genus of up-regulators of CPT2.
DISCLOSURE OF STRUCTURE
The Applicant claims a genus of method for maintaining or improving platelets using the claimed genus of up-regulators of CPT2, but has provided no other up-regulators than the specific 10 individual compounds and the specific single combination, each in specified concentration to maintain or improve platelets. Certainly, a skilled artisan could use any other protein acetylation inhibitors, antioxidants, expression constructs for recombinantly expressing CPT2, up-regulators that promote the driving ability of CPT2 gene promoter, or down-regulators of CPT2 gene-specific microRNA. However, the prior art is silent on using the genus of up-regulators would result in maintaining or improving platelets. Furthermore, neither the specification nor the art indicates a relationship between the structure of the claimed genus of up-regulators and the function of maintaining or improving platelets.
SUFFICIENT RELEVANT IDENTIFYING CHARACTERISTICS
As mentioned above, the skilled artisan could use any up-regulators of CPT2 such as any protein acetylation inhibitors, any antioxidants, any expression constructs for recombinantly expressing CPT2, any up-regulators that promote the driving ability of CPT2 gene promoter, or any down-regulators of CPT2 gene-specific microRNA. However, the prior art is silent on the outcome in maintaining or improving platelets.
The breadth of the claims encompasses a genus of method for maintaining or improving platelets using the claimed genus of up-regulators of CPT2, yet the present specification provides no guidance nor description what up-regulators of CPT2, other than the specific 10 individual compounds and the specific single combination, each in specified concentration, to maintain or improve platelets. Therefore, the skilled artisan would not know what rational approach to take to choose the claimed genus of up-regulators of CPT2, with any predictable outcome on maintaining or improving platelets. Therefore, it is incumbent on the applicant to provide this nexus between structure and function, in order to be given credit for possession of the claimed genus of method for maintaining or improving platelets using the claimed genus of up-regulators of CPT2.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The method of using the claimed invention is not well established. Although an expression construct for recombinantly expressing CPT2 or an up-regulator that promotes the driving ability of CPT2 gene promoter or a down-regulator of CPT2 gene-specific microRNA was known in the state of the art, one of skill in the art would neither expect nor predict the appropriate outcome of maintaining or improving platelets produced according to using the claimed genus of CPT2 up-regulators.
In fact, one of ordinary skill in the art would have appreciated that platelets are cell fragments that lack a nucleus. Thus, although platelets contain translation machinery to enable synthesis of exogenous protein from delivered mRNA, treating platelets with any expression construct, e.g., a plasmid DNA, would not have resulted in recombinantly expressing CPT2 in platelets. Similarly, one of ordinary skill in the art would have immediately expected that treating platelets with an up-regulator that promotes the driving ability of CPT2 gene promoter or a down-regulator of CPT2 gene-specific microRNA, both working at the transcription level, would not have resulted in increasing CPT2 gene transcription and protein production in platelets. Accordingly, the claimed genus of method for maintaining or improving platelets using the claimed genus of up-regulators of CPT2 in platelets, such as an expression DNA construct, an up-regulator that promotes the driving ability of CPT2 gene promoter, or a down-regulator of CPT2 gene-specific microRNA, was not well established.
Applicant has claimed a genus of method for maintaining or improving platelets using the claimed genus of up-regulators of CPT2, yet the present specification has not disclosed such up-regulators of CPT2 other than the specific 10 individual compounds and the specific single combination each in specified concentration that may maintain or improve platelets, has not set forth in terms of distinguishing identifying characteristics as evidenced by other descriptions of the invention that are sufficiently detailed to show that Applicant was in possession of the claimed genus of method. Furthermore, the state of the art indicated that using the claimed genus of up-regulators of CPT2 for maintaining or improving platelets is not well established and would require undue experimentation, and one of skill in the art would neither expect nor predict the claimed function of maintaining or improving platelets produced according to the claimed genus of up-regulators of CPT2.
CONCLUSION
The Examiner concludes that there is insufficient written description of the instantly claimed genus of method for maintaining or improving platelets comprising using or treating with the claimed genus of up-regulators of CPT2. Specifically, Applicant has only provided a limited number of species, i.e., the specific 10 individual compounds and the specific single combination each in specified concentration, thus does not provide a sufficient number of species to represent the entire scope of the claimed extremely broad genus of methods. Therefore, the Examiner concludes that there is insufficient written description to show that Applicant was in possession of the claimed genus of method for maintaining or improving platelets comprising using or treating with the claimed genus of up-regulators of CPT2.
(Scope of Enablement)
Claims 1-5 and 13-16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for maintaining or improving the activity, quality, survival, lifespan or counts of platelets comprising treating the platelets in vitro with a tip60 inhibitor, a p300 inhibitor, NMN, NR, P7C3, SBI-797812, Dorsomorphin, N-acetylcysteine, Mesna, or Glutathione, or a combination of NMN+NAC+Dorsomorphin, each in specified concentration (Example 5, p.29, p. 30-31, Example 6, p. 33, Example 7, p. 34, Examples 8-10, p. 34-35), does not reasonably provide enablement for a genus of method for maintaining or improving the activity, quality, survival, lifespan or counts of platelets comprising using, or treating the platelets with, a genus of up-regulators of CPT2 comprising e.g., any protein acetylation inhibitors, any antioxidants, any expression construct for recombinantly expressing CPT2, any up-regulator that promotes the driving ability of CPT2 gene promoter, or any down-regulator of CPT2 gene-specific microRNA, in any concentration (see e.g. claim 3 and claim 5). The specification does not enable any 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.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The Court in Wands states: “Enablement is not precluded by the necessity for some 'experimentation.'” Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single simple factual determination, but rather is a conclusion reached by weighing many factual considerations.” (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
The office has analyzed the specification in direct accordance to the factors outlined in In re Wands. MPEP 2164.04 states: "[W]hile the analysis and conclusion of a lack of enablement are based on factors discussed in MPEP 2164.01(a) and the evidence as whole, it is not necessary to discuss each factor in written enablement rejection." These factors will be analyzed, in turn, to demonstrate that one of ordinary skill in the art would have had to perform "undue experimentation" to make and/or use the invention and therefore, Applicant's claims are not enabled commensurate with the scope of the invention.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of method for maintaining or improving the activity, quality, survival, lifespan or counts of platelets comprising using or treating with CPT2 or a genus of up-regulator, in any concentration, that comprises e.g., any protein acetylation inhibitors, any antioxidants, any expression construct for recombinantly expressing CPT2, any up-regulator that promotes the driving ability of CPT2 gene promoter, or any down-regulator of CPT2 gene-specific microRNA. However, the specification only discloses and provides guidance for a limited number of species of the method comprising treating the platelets in vitro with 10 specific individual compounds and one specific combination, including a tip60 inhibitor, a p300 inhibitor (Example 5, p.29), NMN, NR, P7C3, SBI-797812 (Example 5, p. 30-31), Dorsomorphin (Example 6, p. 33), N-acetylcysteine, Mesna, Glutathione (Example 7, p. 34), or a combination of NMN+NAC+Dorsomorphin (Examples 8-10, p. 34-35), each in specified concentration. Thus, the specification fails to describe the genus of methods.
ACTUAL REDUCTION TO PRACTICE
Accordingly, Applicant did not demonstrate a reduction to practice of a genus of method for maintaining or improving the activity, quality, survival, lifespan or counts of platelets comprising using or treating with a broad genus of up-regulator of CPT2 that comprises e.g., any protein acetylation inhibitors, any antioxidants, any expression construct for recombinantly expressing CPT2, any up-regulator that promotes the driving ability of CPT2 gene promoter, or any down-regulator of CPT2 gene-specific microRNA. Since the specification only discloses and provides guidance for a limited number of species of up-regulators of CPT2 comprising 10 specific individual compounds and one specific combination, each in specified concentration, the absence of working examples necessitates further experimentation. Therefore, the specification does not provide sufficient guidance on how to use the claimed genus of methods.
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
The state of the art teaches that a method for maintaining or improving platelets using a genus of up-regulators of CPT2 is not a highly successful technique or has highly variable results.
In fact, one of ordinary skill in the art would have appreciated that platelets are cell fragments that lack a nucleus. Thus, although platelets contain translation machinery to enable synthesis of exogenous protein from delivered mRNA, treating platelets with any expression construct, e.g., a plasmid DNA, would not have resulted in recombinantly expressing CPT2 in platelets. Similarly, one of ordinary skill in the art would have immediately expected that treating platelets with an up-regulator that promotes the driving ability of CPT2 gene promoter or a down-regulator of CPT2 gene-specific microRNA, both working at the transcription level, would not have resulted in increasing CPT2 gene transcription and protein production in platelets. Accordingly, the claimed genus of method for maintaining or improving platelets using the claimed genus of up-regulators of CPT2 in platelets, such as an expression DNA construct, an up-regulator that promotes the driving ability of CPT2 gene promoter, or a down-regulator of CPT2 gene-specific microRNA, was not well established.
Furthermore, Applicants are broadly claiming using all up-regulators of CPT2, not just one or two specific up-regulators. However, "the more one claims, the more one must enable." See Amgen v. Sanofi, 143 S.Ct. 1243 (2023). Accordingly, the claims are not enabled for the full breadth of what is being claimed. See Automotive Technologies Int'I, Inc. v. BMW of North America, Inc., 501 F.3d 1274, 185 (Fed. Cir. 2007) (because 'claims must be enabled to correspond to their scope,' a patent on a side-impact crash sensor claiming mechanical and electronic sensors, but enabling only the former, was invalid).
Since the state of the art did not provide guidance for using all up-regulators of CPT2 encompassed by the instant invention, it is incumbent upon the instant specification to do so. The physiological art is recognized as unpredictable (MPEP 2164.03). As set forth in In re Fisher, 166 USPQ 18 (CCPA 1970), compliance with 35 USC 112, first paragraph requires: “That scope of claims must bear a reasonable correlation to scope of enablement provided by specification to persons of ordinary skill in the art; … in cases involving unpredictable factors, such as most chemical reactions and physiological activity, scope of enablement varies inversely with degree of unpredictability of factors involved.” Moreover, the courts have also stated that reasonable correlation must exist between scope of exclusive right to patent application and scope of enablement set forth in the patent application (27 USPQ2d 1662 Ex parte Maize!.). In view of the foregoing, due to the lack of sufficient guidance provided by the specification regarding the issues set forth above, the state of the relevant art, and the breadth of the claims, it would have required undue experimentation for one skilled in the art to use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art teaches that the method for maintaining or improving platelets using a genus of up-regulators of CPT2 is prone to influence by multiple factors, and is highly unpredictable, and the specification does not provide ample guidance, one would be burdened with undue experimentation to use the claimed invention for maintaining or improving platelets using up-regulators of CPT2.
In conclusion, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to use the invention beyond the scope of a method for maintaining or improving the activity, quality, survival, lifespan or counts of platelets comprising treating the platelets in vitro with a tip60 inhibitor, a p300 inhibitor, NMN, NR, P7C3, SBI-797812, Dorsomorphin, N-acetylcysteine, Mesna, or Glutathione, or a combination of NMN+NAC+Dorsomorphin, each in specified concentration.
Examiner’s comment
Based on the limited genus of up-regulators of CPT2 disclosed by Applicant’s specification to have the claimed functional characteristic of maintaining or improving platelets, the prior art Handigund et al., have been applied to anticipate and make obvious this limited genus of method.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-5 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Handigund et al., (Transfus Apher Sci. 2021 Apr; 60(2): 103039, p. 1-7).
With respect to claims 1-5, it is noted that the instant specification recites “the up-regulator of carnitine palmitoyltransferase II includes (but are not limited to) one or more selected from the following group: … antioxidants; preferably including (but are not limited to): N-acetylcysteine (NAC)” (e.g., specification, p. 3), and “antioxidants can reduce reactive oxygen accumulation and indirectly improve the function of CPT2. Therefore, antioxidants can also be used in the present disclosure; preferably including (but are not limited to): N-acetylcysteine” (e.g., specification, p. 13). Therefore, the instant specification discloses that N-acetylcysteine (NAC) is an up-regulator of CPT2 and is an antioxidant capable of increasing/enhancing activity of CPT2.
Handigund teaches a method of reducing the stress induced by cold storage of platelets to extend shelf life of platelets by treating the platelets with N-acetylcysteine (NAC) (see e.g., title and abstract and p. 2, section “2.2. Collection, treatment, and storage of Platelets”). Handigund teaches platelets with NAC showed reduced platelet activation, annexin V binding, ROS production and sialic acid levels, and indicates that NAC addition protects refrigerated platelets during long-term storage retaining the platelet integrity (e.g., abstract, p. 4, section 3.3 “NAC preclude platelet surface markers and ROS generation” and see Fig 3). Thus, Handigund teaches a method for improving storage quality of platelets and prolonging platelet lifespan comprising using an up-regulator of CPT2, i.e., N-acetylcysteine, to the platelets in claim 1, wherein the up-regulator of CPT2 comprises a substance capable of increasing activity of CPT2 in claim 2, wherein the up-regulator of CPT2 comprises an antioxidant in claim 3, and teaches a method for improving quality of platelets stored in vitro, wherein the method comprises treating steps during platelet storage of (b) enhancing activity of CPT2 in claim 4, wherein the method comprises treating with the up-regulator of CPT2 selected from the group of antioxidants in claim 5.
Accordingly, Handigund anticipates instant claims.
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.
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 13-16 are rejected under 35 U.S.C. 103 as being unpatentable over Handigund et al., (Transfus Apher Sci. 2021 Apr; 60(2): 103039, p. 1-7) in view of Kulkarni et al., (Thromb Res. 2020;196:175-185) and Delabie et al., (Transfusion. 2020; 60(1): 165-174).
Claims 13-16 are directed to the up-regulator of CPT2 comprising a combination of nicotinamide mononucleotide (NMN), N-acetylcysteine (NAC) and an AMPK inhibitor. It is noted that the only AMPK inhibitor enabled by the instant specification is Dorsomorphin (also known as Compound C).
As stated supra, Handigund teaches a method for improving storage quality of platelets in vitro comprising treating the platelets with an up-regulator of CPT2, N-acetylcysteine (NAC) (see above).
However, Handigund is silent on combining nicotinamide mononucleotide (NMN) and AMPK inhibitor Dorsomorphin (i.e., Compound C) in treating platelets, nor teach their concentrations or ratio in claims 13-16.
Kulkarni teaches a method of protecting against arterial thrombosis by treating platelets with a specific AMPK inhibitor, compound C (i.e., Dorsomorphin, see e.g., title and abstract), related to claims 13-16. Kulkarni teaches Compound C treatment potently restricted platelet aggregation, clot retraction and integrin activation induced by thrombin and collagen (see abstract, p. 182, section “3.2. CC inhibits platelet aggregation, clot retraction and integrin activation” and section “3.3. Effect of CC on thrombin-stimulated platelets is more pronounced under energy stress”, also see Figs 2-3), indicating Compound C treatment reduces platelet activation, especially under energy stress. Kulkarni teaches upon stimulation, platelets switch their energy metabolism to aerobic glycolysis mediated by AMPK activity and aerobic glycolysis leads to ROS generation (p. 184, right col, para 2), suggesting that AMPK inhibition blocks ROS generation. Kulkarni further teaches the effects of CC are mediated by its influence on ROS-dependent signaling (p. 184, right col, para 3).
Delabie teaches a method of treating platelets with NAD+ precursor nicotinamide riboside (NR) and teaches the treatment increases intracellular level of NAD by almost 10-fold (e.g., abstract). Although Delabie claims treating platelets with NR cannot prevent storage lesion (see title and abstract), Delabie teaches “during aging, NR and control PCs contained increasing numbers of platelets with spontaneously activated integrin αIIbβ3 receptors (Fig. 4A). NR treated platelets were slightly less activated than control platelets and this was significant from Day 19 on (p ≤ 0.01)” (p. 168, right col, section “Influence of NR on platelet activation”, also see Fig 4A-4B attached) and teaches Bcl-xL is an anti-apoptotic protein and Fig 6B demonstrates that the Bcl-xL level in NR-treated platelets is significantly higher than control group from Day 19 (see Fig 6B attached, arrows added by examiner showing statistically significant differences). Thus, Delabie demonstrates that NR treatment significantly reduces platelet activation (Fig 4) and likely reduces apoptosis by the significantly higher level of anti-apoptotic protein Bcl-xL (Fig 6B). Delabie acknowledges that both nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are niacin precursors and both have been shown to increase viability of cells, tissues, and entire organisms (p. 166, left col, para 2), related to claims 13-16.
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Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method for improving storage quality of platelets comprising treating with N-acetylcysteine (NAC) disclosed by Handigund, by combining AMPK inhibitor compound C (i.e., Dorsomorphin) as suggested by Kulkarni and combining a NAD+ precursor as suggested by Delabie with a reasonable expectation of success. Since Handigund teaches platelets treated with NAC have improved storage quality demonstrated by reduced platelet activation, reduced annexin V binding (i.e., reduced apoptosis) and reduced ROS production (see above), since Kulkarni indicates Compound C treatment reduces platelet activation especially under energy stress and suggests that AMPK inhibition blocks ROS generation (see above), and since Delabie demonstrates that NAD+ precursor NR treatment significantly reduces platelet activation (Fig 4) and likely reduces apoptosis by the significantly higher level of anti-apoptotic protein Bcl-xL (Fig 6B), one of ordinary skill in the art would have had a reason to combine an AMPK inhibitor compound C (i.e., Dorsomorphin) as suggested by Kulkarni and a NAD+ precursor (e.g., NR) as suggested by Delabie with N-acetylcysteine (NAC) disclosed by Handigund to treat platelets in order to further reduce platelet activation, ROS production and apoptosis to improve storage quality of platelets.
Furthermore, since Delabie acknowledges that nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) are both niacin precursors and have been shown to increase viability of cells, tissues, and entire organisms (p. 166, left col, para 2), these compounds are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted nicotinamide mononucleotide (NMN) for nicotinamide riboside (NR). See MPEP 2144.06.
In regard to the concentrations of the three compounds in claim 16, Handigund teaches 50 mM NAC (e.g., p. 2, left col, para 2.2), within the claimed range. Kulkarni teaches the compound C at a concentration of 10 µM (e.g., p. 177, last para), within the claimed range. Delabie teaches 154 nmol of NR was added per 109 platelets per day (e.g., p. 166, left col, last para), within the claimed range.
Accordingly, one of ordinary skill in the art would have chosen the taught concentrations of the compounds with a reasonable expectation of success. Since Handigund, Kulkarni and Delabie reduce to practice the concentrations that are within the claimed ranges of the compounds in treating platelets, one of ordinary skill in the art would have had a reason to choose the taught concentrations to treat platelets.
Furthermore, regarding the molar ratio of the compounds in claims 14 and 16, MPEP states “generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” and “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 MPEP 2144.05(II)(A). In the instant case, Handigund, Kulkarni and Delabie have reduced to practice the concentrations, that are within the claimed ranges, of the compounds in treating platelets. Therefore, it would have been obvious for one ordinary skill in the art before the effective filing date of the claimed invention to apply the three compounds in the claimed molar ratio because they are the result of “routine optimization”.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631
