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 .
Election/Restrictions
Applicant’s election without traverse of Group 2 related to biological methods (claims 1-2, 5-7, and 9-10), the species of adeno-associated virus (claim 5) and species of microRNA (claim 9) in the reply filed on November 24, 2025 is acknowledged. It is noted that Applicant has not identified traversal and thus, the elections are being treated as without traverse.
Claims 3-4 and 8 have been canceled.
Claims 1-2, 5-7, and 9-10 are examined on the merits.
Priority
The instant application is a 35 U.S.C 371 national stage filing of the International Application No. PCT/CN2021/130496 filed on November 14, 2021. The instant application claims foreign priority under 35 U.S.C 119(a)-(d) to Chinese Patent Application CN202011274161.1, filed on November 15, 2020. Receipt is acknowledged of a certified copy of the foreign patent application in the original language as required by 37 CFR 1.55.
Information Disclosure Statement
No Information Disclosure Statement (IDS) has been filed with the instant application.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Objections to the Specification
The use of the term Thermo Scientific Phusion on Pg 5, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 1 is objected to because of the following informalities: CNPase appears to be the abbreviation for the term 2’, 3’-cyclic nucleotide-3’-phosphodiesterase. Terms should be defined by use of the full term at the first recitation followed by the abbreviation in parentheses. Thereafter the abbreviation can be used for all subsequent recitations. Appropriate correction is required. It is recommended that Applicant amend Claim 1 to recite “2’, 3’-cyclic nucleotide-3’-phosphodiesterase (CNPase)”.
Claim 2 is objected to because of the following informalities: as written, claim 2 defines heart disease as requiring chronic myocardial ischemia, myocardial hypertrophy, chronic heart failure, and myocardial remodeling. If this is intended be a Markush group of alternatives, it is recommended that Applicant amend the claim to recite “…wherein the said heart disease includes chronic myocardial ischemia, myocardial hypertrophy, chronic heart failure, or myocardial remodeling” or “…wherein the said heart disease is selected from the group consisting of chronic myocardial ischemia, myocardial hypertrophy, chronic heart failure, and myocardial remodeling”.
Claim 7 is objected to because of the following informalities: 2’, 3’-cAMP; 2’, 3’-cGMP; 2’ 3’-cCMP; and 2’ 3’-cIMP appear to be abbreviations. Terms should be defined by use of the full term at the first recitation followed by the abbreviation in parentheses.
Claim 7 is objected to because of the following informalities: as written, claim 7 defines related substrates of CNPase as requiring 2’, 3’-cAMP; 2’, 3’-cGMP; 2’ 3’-cCMP; and 2’ 3’-cIMP. If this is intended be a Markush group of alternatives, it is recommended that Applicant amend the claim to recite “…the concentration of related substrates including 2’, 3’-cAMP; 2’, 3’-cGMP; 2’ 3’-cCMP; or 2’ 3’-cIMP” or “…the concentration of related substrates is selected from the group consisting of 2’, 3’-cAMP; 2’, 3’-cGMP; 2’ 3’-cCMP; and 2’ 3’-cIMP”.
Claim Interpretation
Claim 2, as instantly claimed, does not comprise heart diseases recited in the alternative. As such, claim 2 requires heart disease which consists of myocardial ischemia, myocardial hypertrophy, heart failure, and myocardial remodeling are present at the same time.
Claim 7, as instantly claimed, does not comprise substrates recited in the alternative. As such, claim 7 requires decrease of the absolute amount or concentration of substrates 2’ 3’-cAMP, 2’ 3’-cGMP, 2’ 3’-cCMP, and 2’ 3’-cIMP.
Claim 10, as instantly claimed, only requires “intravenous, inhalation, or myocardium local injection of a pharmaceutical excipient/carrier” which is characterized by a pharmaceutical formulation of injectable solution, injectable dry powder, or “other combined releasing agents”.
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 5-7 and 9-10 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.
Claim 5, which depends from claim 1, recites the limitation "CNPase" in line 3. There is insufficient antecedent basis for this limitation in the claim as the prior recitation is to myocardial CNPase. As written, it is unclear if CNPase is intended to refer to CNPase located in myocardium or global CNPase. Appropriate correction is required.
Claims 5 and 6, which depend from claim 1, recite the limitation "increase the activity and expression" in lines 3 and 2, respectively. There is insufficient antecedent basis for this limitation in the claim as the prior recitation is to increasing the activity or expression. Appropriate correction is required.
Claim 6, which depends from claim 1, recites the limitation "CNPase" in line 2. There is insufficient antecedent basis for this limitation in the claim as the prior recitation is to myocardial CNPase. As written, it is unclear if CNPase is intended to refer to CNPase located in myocardium or global CNPase. Appropriate correction is required.
Claim 7, which depends from claim 1, recites the limitation “related substrates including 2’, 3’-cAMP, 2’ 3’-cGMP, 2’ 3’-cCMP, and 2’ 3’ -cIMP” which renders the scope of the claim indefinite. As written, it is unclear if 2’, 3’-cAMP, 2’ 3’-cGMP, 2’ 3’-cCMP, and 2’ 3’ -cIMP are intended to refer to exemplary “related substrates” or to further define the related substrates which are decreased as 2’, 3’-cAMP, 2’ 3’-cGMP, 2’ 3’-cCMP, and 2’ 3’ -cIMP. Appropriate correction is required.
Claim 9, which depends from claims 6 and 1, recites the limitation "increase the activity" in line 4. There is insufficient antecedent basis for this limitation in the claim as the prior recitation in claim 6 is to increasing the activity and expression and the prior recitation in claim 1 is to increasing the activity or expression. Appropriate correction is required.
Claim 9, which depends from claims 6 and 1, recites the limitation "CNPase" in line 4. There is insufficient antecedent basis for this limitation in the claim as the prior recitation in claim 1 is to myocardial CNPase. As written, it is unclear if CNPase is intended to refer to CNPase located in myocardium or global CNPase. Appropriate correction is required.
Claim 10, which depends from claim 1, recites the limitation "pharmaceutical excipient/carrier" in line 4 which renders the scope of the claim indefinite. As written, it is not clear whether the “/” is intended to refer to a pharmaceutical excipient and carrier, a pharmaceutical excipient or carrier, or a pharmaceutical excipient and/or carrier. Appropriate correction is required.
Claim 10, which depends from claim 1, recites the phrase "other combined releasing agents" in line 6 which renders the claim indefinite. The phrase “combined releasing agents” is not defined by the claim, the specification does not provide a standard for measuring the scope of the term, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 112(a) – Scope of Enablement
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 1-2, 5-7, and 9-10 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 increasing the expression of CNPase via use of an AAV9-CNPase and subsequent effects related to treatment of indicators of myocardial hypertrophy and myocardial remodeling, does not reasonably provide enablement for increasing the activity or expression of myocardial CNPase via all biological methods, including use of non-coding RNA, specifically microRNA, or by decreasing the amount or concentration of substrates of CNPase via intravenous, inhalation, or myocardium local injection of a pharmaceutical excipient/carrier which is an injectable solution, injectable dry power, or other combined releasing agents. 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.
SCOPE OF THE INVENTION
The breadth of the claims encompasses a genus of biological methods which can be used to increase the activity or expression of myocardial CNPase for the treatment of heart disease. As discussed supra, the specification fails to describe the genus of biological methods and would require undue experimentation to discover these biological methods. The specification only discloses and provides guidance for increased expression of CNPase via an AAV9-CNPase as it relates to treatment of indicators of myocardial hypertrophy and myocardial remodeling.
Independent claim 1 encompass a genus of biological methods which can be used to increase the activity or expression of myocardial CNPase for the treatment of heart disease, while the specification only discloses a single biological method of an AAV9-CNPase, which presumably increases expression of CNPase, and treatment of indicators of myocardial hypertrophy and myocardial remodeling.
Dependent claim 2 encompasses a genus of heart diseases while the specification only discloses effects on indicators of myocardial hypertrophy and myocardial remodeling.
Dependent claims 5, 6 and 8 encompass a genus of biological methods used to increase the activity and/or expression of myocardial CNPase including adeno associated virus and non-coding RNA, specifically microRNA, while the specification only discloses an AAV9-CNPase, which presumably increases expression of CNPase.
Dependent claim 7 encompasses a genus methods of increasing the activity or expression of myocardial CNPase via decreasing the absolute amount or concentration of related substrates including 2’, 3’-cAMP, 2’ 3’-cGMP, 2’ 3’-cCMP, and 2’ 3’ -cIMP, while the specification is silent as to alterations of these substrates in the method.
Dependent claim 10 encompasses a genus of methods of increasing the activity or expression of myocardial CNPase via biological methods via intravenous, inhalation, or myocardium local injection of a pharmaceutical excipient/carrier which is an injectable solution, injectable dry powder, or other combined releasing agents, while the specification is silent as to administration of any pharmaceutical excipient/carrier.
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.
ACTUAL REDUCTION TO PRACTICE
The specification does not provide guidance for or a working example for increased activity of myocardial CNPase by any biological methods which can be used to treat heart disease and only provides an embodiment of an AAV9-CNPase which is presumed to increase CNPase expression, although it is noted that Applicant’s instant specification has not provided data showing measurement of activity or expression of CNPase nor the localization of CNPase. Further, Applicant has only provided data related to the effects of administration of the AAV9-CNPase after abdominal aortic ligation, which provides indicators of myocardial hypertrophy (Example 2) and myocardial remodeling (Example 3). Further, Applicant only mentions that the AAV9-CNPase was “given” (Pg. 7, last para.) by “targeted injection” (Pg. 3) but does not provide the location, route, or details of administration. The absence of working examples directed to use of AAV9-CNPase to increase enzyme activity and for treatment of other indicators of heart disease necessitates further experimentation. Additionally, no working examples were provided that utilize biological methods that are not AAV9-CNPase (i.e., non-coding RNA, microRNA) or that increase activity of CNPase by decreasing the amount or concentration of CNPase substrates 2’ 3’-cAMP, 2’ 3’-cGMP, 2’ 3’-cCMP, and 2’ 3’-cIMP as well as no working examples where administration of a pharmaceutical excipient/carrier is responsible for the effect. Therefore, the specification does not provide sufficient guidance on how to make and use the claimed method.
In regard to claim 1 encompassing a genus of biological methods which can be used to increase the activity or expression of myocardial CNPase for the treatment of heart disease, the specification discloses use of an AAV9-CNPase, which presumably increases expression of CNPase, and the effect on a single indicator of myocardial hypertrophy (heart weight/body weight ratio; Example 2, Table 1) and single indicator of myocardial remodeling (percentage of interstitial fibrosis; Example 3, Table2) in response to abdominal aortic ligation.
In regard to dependent claim 2 encompassing a genus of heart diseases, the specification only discloses the effect on a single indicator of myocardial hypertrophy (heart weight/body weight ratio; Example 2, Table 1) and single indicator of myocardial remodeling (percentage of interstitial fibrosis; Example 3, Table2)
In regard to dependent claims 5, 6 and 8 encompassing a genus of biological methods used to increase the activity and/or expression of myocardial CNPase including adeno associated virus and non-coding RNA, specifically microRNA, the specification only discloses an AAV9-CNPase (Pgs., 5-6, Construction of AAV9-CNPase plasmid, Examples 1-4), which presumably increases expression of CNPase although it is noted that the specification does not provide data related to measurement of CNPase or localization.
In regard to dependent claim 7 encompassing a genus methods of increasing the activity or expression of myocardial CNPase via decreasing the absolute amount or concentration of related substrates including 2’, 3’-cAMP, 2’ 3’-cGMP, 2’ 3’-cCMP, and 2’ 3’ -cIMP, the specification is silent as to alterations of these substrates.
In regard to dependent claim 10 encompassing a genus of methods of increasing the activity or expression of myocardial CNPase via biological methods via intravenous, inhalation, or myocardium local injection of a pharmaceutical excipient/carrier which is an injectable solution, injectable dry powder, or other combined releasing agents, the specification is silent as to administration of any pharmaceutical excipient/carrier and only discloses that the AAV9-CNPase was “given” (Pg. 7, last para.) by “targeted injection” (Pg. 3).
STATE OF THE ART & QUANTITY OF EXPERIMENTATION
In fact, the state of the art teaches that methods of increasing activity or expression of CNPase via any biological method for treatment of heart disease is not a highly successful technique or has highly variable results. Consequently, there is ample reason to conclude that there would be a high degree of unpredictability in the method of using the genus of biological methods to increase activity or expression of CNPase for the treatment of the genus of heart diseases claimed the instant invention. Since the prior art at the effective filing date of the present application did not provide guidance for increasing activity or expression of CNPase via any biological method for treatment of any heart disease, it is incumbent upon the instant specification to do so.
Jackson et al. (2016, Renal 2′, 3′-cyclic nucleotide 3′-phosphodiesterase is an important determinant of AKI severity after ischemia-reperfusion. J. of the ASoN, 27(7), 2069-2081), teaches that CNPase knockout mice exhibit less severe effects from ischemia-reperfusion injuries in kidney indicating that reduction in CNPase is beneficial in prevention of ischemia induced damage, at least in kidney tissue, in response to ischemic injury (Abstract). Jackson et al. teaches that the protective effect of inhibition of CNPase is thought to be due enhanced autophagy and the ability to quickly remove damaged mitochondria in response to injury (Pg. 2076, right col., top para.).
Olga et al. (2020, The functions of mitochondrial 2′, 3′-cyclic nucleotide-3′-phosphodiesterase and prospects for its future. Intl. J. of Mol. Sci., 21(9), 3217) teaches that mitochondrial disruption is implicated in cardiovascular disorders (Pg. 9, 2nd para.) and that although mPTP is known to play a role in cardiac protection and has been considered a target of therapeutics, the complexity surrounding the regulation of mPTP in the heart has limited further understanding (Pg. 9, 3rd para.). Olga teaches that CNPase plays a role in the functioning of mPTP and that mPTP inhibition is considered to be cardioprotective (Pg. 9, 4th para.). Further, Olga teaches that levels of CNPase decrease with age and that CNPase increased in heart mitochondria of aged rats with acute heart failure (Pg. 9, last para. and Pg. 10, 1st para.) However, treatment with AST, which improved mitochondrial function and inhibited apoptosis, decreased CNPase (Pg. 10, 2nd and 3rd paras.).
Li et al. (2019, 2', 3'‐Cyclic‐nucleotide 3'‐phosphodiesterase contributes to epithelial‐mesenchymal transition of lens epithelial cells through the notch signaling pathway. Cell Proliferation, 52(6), e12707) teaches that fibrosis is a common cause of organ dysfunction and failure and that the epithelial-mesenchymal transition (EMT) is a major contributor to organ fibrosis (Pg. 1., left col.). Li et al. teaches that lens fibrosis, caused by EMT, plays a role in development of cataracts (Pg. 2, left col., 1st para.) and that increased CNPase expression is upregulated in in EMT and cataract development (Figure 1C & D, Pg. 10, left col., 1st para. and right col.) and CNPase knockdown inhibited expression of EMT markers (Figure 3 and Pg. 11, left col., 2nd para.), indicating that increased CNPase is associated with increased fibrosis.
Additionally, Applicant’s specification indicates that the abdominal aortic ligation model of myocardial hypertrophy does not alter the expression of CNPase protein but decreases the activity of the enzyme (Pg. 2, 2nd full para.). Thus, the prior art, as well as Applicant’s specification, indicate that the role of CNPase in as it relates to protective effects as well as its role in heart disease is complex, and one of ordinary skill would not have predictably used any biological method to increase activity or expression of myocardial CNPase to treat any type of heart disease.
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(a) 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 predictable factors, such as mechanical or electrical elements, a single embodiment provides broad enablement in the sense that, once imagined, other embodiments can be made without difficulty and their performance characteristics predicted by resort to known scientific laws; 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 make and use the instant broadly claimed invention.
CONCLUSION
In conclusion, since the art teaches that success of said method is prone to influence by multiple factors, and is highly unpredictable with respect to treatment of all heart diseases by any biological method, and the specification does not provide ample guidance with respect to achieving the unexpected results, one would be burdened with undue experimentation to use the claimed method of increasing activity or expression of myocardial CNPase via biological methods for treatment of heart diseases as broadly as instantly claimed. Therefore, given the breadth of the claims and the limited scope of the specification, an undue quantity of experimentation is required to make and use the invention beyond the scope of increasing CNPase via administration of an AAV9-CNPase for the treatment of myocardial hypertrophy and associated myocardial remodeling caused by abdominal aortic ligation.
Conclusion
No claims are allowed.
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/ERIN V PAULUS/Examiner, Art Unit 1631
/ARTHUR S LEONARD/Examiner, Art Unit 1631
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