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 .
Applicant’s amendment and response filed on 11/10/2025 has been received and entered into the case.
Claims 1-23 have been considered on the merits. All arguments have been considered.
Claim Objections
Claim 1 is objected to because of the following informalities: the term “Methylpseudouridine” in line 5 would be “methylpseudouridine” instead. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
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 1-23 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claims 1-11 and 20-23 are directed to a method of preventing heart failure in a subject having cardiac hypertrophy or dilated cardiomyopathy by administering a modRNA encoding pip4k2c to heart tissue of the subject.
The instant specification does not particularly limit or define the term “heart failure” and the scope of the term. The term “heart failure” is interpreted as cardiomyopathy which includes “dilated cardiomyopathy” and “hypertrophic cardiomyopathy”. Furthermore, the instant specification discloses that the heart failure treated by methods disclosed herein is dilated cardiomyopathy (DCM).
There is no disclosure in the instant specification that the administration of a modRNA encoding pip4k2c would prevent heart failure in a subject having dilated cardiomyopathy.
In amended cases, subject matter not disclosed in the original application is sometimes added and a claim directed thereto. Such a claim is rejected on the ground that it recites elements without support in the original disclosure under 35 U.S.C. 112, first paragraph, Waldemar Link, GmbH & Co. v. Osteonics Corp. 32 F.3d 556, 559, 31 USPQ2d 1855, 1857 (Fed. Cir. 1994); In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981). See MPEP § 2163.06 - § 2163.07(b) for a discussion of the relationship of new matter to 35 U.S.C. 112, first paragraph. New matter includes not only the addition of wholly unsupported subject matter, but may also include adding specific percentages or compounds after a broader original disclosure, or even the omission of a step from a method. See MPEP § 608.04 to § 608.04(c). See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976) and MPEP § 2163.05 for guidance in determining whether the addition of specific percentages or compounds after a broader original disclosure constitutes new matter.
Claims 1-23 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Preventing heart failure (claims 1-11 and 20-23):
Claims 1-11 and 20-23 are directed to a method of preventing heart failure in a subject having cardiac hypertrophy or dilated cardiomyopathy by administering a modRNA encoding pip4k2c to heart tissue of the subject.
The claimed subject is required to have cardiac hypertrophy or dilated cardiomyopathy. Thus, the scope of claimed method is limited to the subject already suffering from cardiac hypertrophy or dilated cardiomyopathy and the heart failure is prevented from the subject by administering a modRNA encoding pip4k2c.
The instant specification discloses Examples and data showing the elevated level of pip4k2c and attenuation of cardiac hypertrophy and fibrosis post TAC injury, and the specification discloses “as shown in Examples 1-5 below, increased expression of Pip4k2c significantly attenuated and/or prevented cardiac hypertrophy and fibrosis in the failing heart and improved cardiac function via inhibition of mTORC1 and TGFb activity - two independent signaling pathways activated in heart failure and other cardiac diseases” (para. 135). The instant specification discloses that the expression of modified mRNA encoding PIP4k2c would reduce or attenuate the development of cardiac hypertrophy and fibrosis. Particularly Example 4 is directed to the overexpression of PIP4K2C modRNA in TAC operated mice. Figure 29 of the instant application was disclosed to show that the administration of PIP4K2C modRNA significantly attenuated and/or prevented cardiac hypertrophy and fibrosis in the failing heart and improved cardiac function. However, the figure does not provide any evidence that the overexpression of PIP4K2C “prevented” heart failure in the mice having cardiac hypertrophy after the TAC operation. Rather, according to Fig. 19, it appears that modRNA injection is a day after TAC. It is understood that cardiac hypertrophy is developing 1-2 weeks post TAC operation according to deAlmeida et al. (2010, JOVE; IDS ref.; see p.2, 6:Representative Results). Therefore, Example 4 and the corresponding figure 19 are understood that in the presence of overexpressing PIP4K2C, TAC operation reduces the occurrence of cardiac hypertrophy in the mice. This is not consistent with the claimed subject of “a subject having cardiac hypertrophy or dilated cardiomyopathy” as claimed.
Thus, while the instant application provides evidence that cardiac hypertrophy was attenuated by overexpression of PIP4K2C, but fails to provide sufficient written description to support “prevention” of heart failure in a subject having cardiac hypertrophy.
The scope of “treatment of heart failure” (claims 12-19):
The specification does not provide any definition to the term “treatment” disclosed in claims 12-19 with regard to the scope of the term.
The claims are understood that the claimed composition would necessarily and sufficiently “treat” heart failure in any subject that is treated with the claimed composition. Thus, the term “treatment” disclosed in the instant claims is interpreted broadly to encompass not only reducing or alleviating any symptoms of the heart failure but also curing and/or preventing heart failure in any subject.
As discussed above, the instant specification discloses Examples using a mouse model, i.e. TAC, which induces cardiac hypertrophy, and the presence of PIP4K2C overexpression, the mouse model of TAC would have reduced/attenuated heart failure.
The instant specification discloses “[t]o date, the only treatment regimens for heart failure are to prevent further damage by controlling blood pressure, reducing the occurrence of arrhythmias, and preventing blood clots from forming. There no medications that reverse the weakened heart muscle. For those with severe DCM, the only treatments are invasive such as surgical repair of the left ventricle or implantation of biventricular pacemakers and cardioverter defibrillators. For subjects with advanced heart failure, such surgical interventions and be risky and it is unclear whether such surgical treatment always improves long-term outcomes. As such, there is a need for less invasive therapies that not only treat heart failure but can also improve cardiac muscle function.” (para. 5) This disclosure and the rest of the specification indicates that the claimed method is only intended to alleviating the symptoms and preventing further damage, arrhythmias and/or blood clots. In fact, it is well known in the art that heart failure cannot be prevented by any therapeutic treatment or there is no cure for the heart failure.
Considering broad scope of the term “treatment” in the claimed invention as discussed above, and the lack of description how the broad scope of “treatment” which encompasses preventing and curing of a heart failure, it is considered that the instant specification fails to provide sufficient written description for the entire scope of the claimed invention.
The instant specification discloses the decreased pip4k2c expression in failing hearts of humans having cardiac hypertrophy (CH) and dilated cardiomyopathy (DCM) (Figure 1; para. 14). The specification further showed the decreased pip4k2c expression in failing hearts of mice (cardiomyocytes and fibroblasts), and the mice were TAC mouse models of heart failure (Fig. 2; para. 15; Example 2). Thus, the heart failure in mouse and human induces decrease of pip4k2c expression.
Example 3 of the instant specification discloses the data showing the difference between pip4k2c-KO mice vs. WT with or without TAC in their fractioning shorting, LVIDd, LVIDs, and delta% left ventricular ejection fraction (Fig. 5). It appears that these data show the deficiency of pip4k2c in a knockout mouse deteriorates cardiac function more in the KO mice compared to WT mice.
Example 4 of the specification discloses that the expression of modRNA encoding pip4k2c reversed the cardiac hypertrophy and fibrosis in the TAC mice model (WT mice) (Figs. 13-14).
Based on the disclosed experimental data, the instant specification provides sufficient written description for the claimed invention with regard to a mouse model. However, there is no disclosure with regard to any other subject encompassed by the claimed invention including human. As discussed above, the specification shows that pip4k2c expression were decreased in humans having cardiac hypertrophy and dilated cardiomyopathy. However, there is no disclosure if the expression of modRNA encoding pip4k2c in the humans having heart failure would be improved, let alone prevented or cured, as shown in a mouse model. Thus, the instant specification failed to provide sufficient written description for the entire scope of the claimed invention.
M.P.E.P. §2163 states “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.”
M.P.E.P. § 2163 also recites, “An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention… one must define a compound by ‘whatever characteristics sufficiently distinguish it’. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process.” and further, “The description needed to satisfy the requirements of 35 U.S.C. 112 "varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence." Capon v. Eshhar, 418 F.3d at 1357, 76 USPQ2d at 1084.< Patents and printed publications in the art should be relied upon to determine whether an art is mature and what the level of knowledge and skill is in the art. In most technologies which are mature, and wherein the knowledge and level of skill in the art is high, a written description question should not be raised for claims >present in the application when originally filed,< even if the specification discloses only a method of making the invention and the function of the invention. See, e.g., In re Hayes Microcomputer Products, Inc. Patent Litigation, 982 F.2d 1527, 1534-35, 25 USPQ2d 1241, 1246 (Fed. Cir. 1992) ("One skilled in the art would know how to program a microprocessor to perform the necessary steps described in the specification. Thus, an inventor is not required to describe every detail of his invention. An applicant's disclosure obligation varies according to the art to which the invention pertains. Disclosing a microprocessor capable of performing certain functions is sufficient to satisfy the requirement of section 112, first paragraph, when one skilled in the relevant art would understand what is intended and know how to carry it out."). In contrast, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession.”
Scope of Enablement Rejection
Claims 1-11 and 20-23 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 reduce the occurrence of cardiac hypertrophy in a mouse model having transverse aortic constriction (TAC), does not reasonably provide enablement for preventing heart failure in a subject including human having cardiac hypertrophy or dilated cardiomyopathy. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized in In re Wands, 858 F.2d 731, 737, 8 USPQd 1400, 1404 (Fed. Cir. 1988) (a) the breadth of the claims; (b) the nature of the invention; (c) the state of the prior art; (d) the level of one of ordinary skill; (e) the level of predictability in the art; (f) the amount of direction provided by the inventor; (g) the existence of working examples; and (h) the quantity of experimentation needed to make or use the invention based on the content of the disclosure. While all of these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
(a) the breadth of the claims:
The instant claims are directed to a method of preventing a heart failure by administering a modRNA encoding pip4k2c to heart tissue of a subject having cardiac hypertrophy or dilated cardiomyopathy.
The instant specification does not particularly limit or define the term “heart failure” and the scope of the term. The term “heart failure” is interpreted as cardiomyopathy which includes “dilated cardiomyopathy” and “hypertrophic cardiomyopathy”. In fact, the instant specification discloses that the heart failure treated by methods disclosed herein is dilated cardiomyopathy (DCM). As discussed (see 35 U.S.C. 112(a), written description rejection above and the 112b rejection below), it is not clear how the claimed method would “prevent” in a subject who already has heart failure, i.e. dilated cardiomyopathy. Rather it appears that the claimed invention is directed to a method of preventing heart failure in a subject having cardiac hypertrophy as it is known in the art that the onset of heart failure is typically preceded by cardiac hypertrophy (see Tham et al. 2015, Arch. Toxicol.).
The claimed method does not particularly limit the scope of the subject being administered with the modRNA encoding pip4k2c, and thus, the scope of the subject is broad to encompass any mammal including human.
(b) the nature of the invention:
The claimed invention is directed to a method of administering modRNA encoding pip4k2c in order to treat heart failure in a subject in need thereof. The claimed invention does not particularly limit the subject so the scope of the subject being treated with the modRNA encoding pip4k2c would be any mammal including a human.
The subject as claimed in the amended claims is required to have cardiac hypertrophy or dilated cardiomyopathy. Thus, the expression of PIP4K2C in the subject having cardiac hypertrophy would be prevented to develop heart failure.
(c) the state of the prior art:
While the use of modRNA is known in the art, however, it is not known in the art at the time of filing that pip4k2c expression would prevent heart failure in any subject having cardiac hypertrophy or dilated cardiomyopathy. Furthermore, as discussed in the instant specification, “[t]o date, the only treatment regimens for heart failure are to prevent further damage by controlling blood pressure, reducing the occurrence of arrhythmias, and preventing blood clots from forming. There no medications that reverse the weakened heart muscle. For those with severe DCM, the only treatments are invasive such as surgical repair of the left ventricle or implantation of biventricular pacemakers and cardioverter defibrillators. For subjects with advanced heart failure, such surgical interventions and be risky and it is unclear whether such surgical treatment always improves long-term outcomes. As such, there is a need for less invasive therapies that not only treat heart failure but can also improve cardiac muscle function.” (para. 5)
(d) the level of one of ordinary skill:
The level of one of ordinary skill in the art at the time of invention was advanced, being that of a person holding a Ph.D. or an M.D.
(e) the level of predictability in the art:
It is highly unpredictable that the expression of modRNA encoding pip4k2c would necessarily and sufficiently prevent heart failure in the human subject having cardiac hypertrophy or dilated cardiomyopathy. The Example of the instant specification shows that when the overexpression of PIP4K2C is present right after the TAC operation in mice, the occurrence of cardiac hypertrophy is reduced and thus, the survival of the mice would be improved. While it is evident that there is a functional importance of PIP4K2C expression, however, the data shown in Example 4 are not commensurate with the claimed scope of preventing heart failure in a subject having cardiac hypertrophy or dilated cardiomyopathy. This is because the experimentation was designed that the overexpression was already in mice before the development of cardiac hypertrophy caused by TAC operation in mice. Thus, at most, PIP4K2C expression would attenuate cardiac hypertrophy in TAC mice but not the mice having cardiac hypertrophy.
As discussed, the subject is not limited to mice, and rather it would also encompass human patients. However, there is no indication that the effect in a mouse model would absolutely translate into human treatment. It is quite well known in the art that translational failure is common in HF research; therapies with efficacy in preclinical models have failed when applied to human clinical trials according to Bosch et al. (2021, Heart Failure Review). In the absence of clear correlation or evidence that the therapeutic efficacy shown in a mouse model would necessarily translate into a human treatment, the effective therapeutic outcome in human having heart failure by using the claimed method or the delivery system is highly unpredictable.
The court has recognized that physiological activity is unpredictable. In re Fisher, 166 USPQ 18 (CCPA 1970). 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. In re Fisher, 166 USPQ 18 (CCPA 1970).
It is not to be left up to the skilled artisan to figure out how to make the necessary starting materials and then to figure out how to use them to produce the biological effects as recited in the claims. The courts held that the disclosure of an application shall inform those skilled in the art how to use applicant's claimed invention, not how to find out how to use it for themselves. In re Gardner et al. 166 USPQ 138 (CCPA 1970). For the broad scope of the claims, this specification only teaches what is intended to be done and how it is intended to work, but does not actually teach how to do that which is intended.
(f) the amount of direction provided by the inventor/(g) the existence of working examples:
The instant specification discloses the decreased pip4k2c expression in failing hearts of humans having cardiac hypertrophy (CH) and dilated cardiomyopathy (DCM) (Figure 1; para. 14). The specification further showed the decreased pip4k2c expression in failing hearts of mice (cardiomyocytes and fibroblasts), and the mice were TAC mouse models of heart failure (Fig. 2; para. 15; Example 2). Thus, the heart failure in mouse and human induces or causes the decreased expression of pip4k2c.
Example 3 of the instant specification discloses the data showing the difference between pip4k2c-KO mice vs. WT with or without TAC in their fractioning shorting, LVIDd, LVIDs, and delta% left ventricular ejection fraction (Fig. 5). It appears that these data show the deficiency of pip4k2c in a knockout mouse deteriorates cardiac function more in the KO mice compared to WT mice.
Example 4 of the instant specification shows that when the overexpression of PIP4K2C is present right after the TAC operation in mice, the occurrence of cardiac hypertrophy is reduced and thus, the survival of the mice would be improved.
Based on the disclosed experimental data, the instant specification provides sufficient written description for the claimed invention with regard to a mouse model and the improvement in attenuating cardiac hypertrophy in the TAC operated mice.
However, as discussed above, there is no showing for the subject having cardiac hypertrophy or dilated cardiomyopathy in the mouse model.
Furthermore, there is no disclosure with regard to any other subject encompassed by the claimed invention including human. As discussed above, the specification shows that pip4k2c expression were decreased in humans having cardiac hypertrophy and dilated cardiomyopathy. However, there is no disclosure if the expression of modRNA encoding pip4k2c in the humans having heart failure would be improved, and this deficiency is present even in the mouse model.
The results or outcomes including survival rate or life expectancy as claimed in the instant invention are based on the data presented in the instant specification, and these data are obtained from a TAC mouse model when the PIP4K2C is expressed right after the TAC operation. This is the time point when cardiac hypertrophy is not even evident in the operated mice. There is no expectation that the claimed method would result in the mice fully developed with cardiac hypertrophy post-TAC, let alone in human subject having cardiac hypertrophy or dilated cardiomyopathy.
Based on the above discussion, it has been concluded that the instant specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims without undue experimentations.
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 1-11 and 20-23 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 discloses that the claimed method prevents heart failure in a subject having cardiac hypertrophy or dilated cardiomyopathy. It is not clear if the preamble of the claim is intended to “preventing heart failure in a subject having cardiac hypertrophy or preventing dilated cardiomyopathy”; or the subject having either “cardiac hypertrophy” or “dilated cardiomyopathy”. Clarification is required. If it is the latter, it is not clear how the subject that already has heart failure would be prevented. The instant specification discloses the heart failure treated by methods disclosed herein is dilated cardiomyopathy (DCM) (para. 11-12). Thus, the subject having dilated cardiomyopathy would be considered as the subject having heart failure. Clarification is required.
Response to Arguments
Applicant’s arguments with respect to claim(s) 1-23 have been considered but are moot due to the instant amendment which necessitates new ground of rejection.
Applicant is advised to amend claim 1 to, for example, “A method of attenuating cardiac hypertrophy in a subject at risk of developing heart failure, the method comprising…”
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/TAEYOON KIM/Primary Examiner, Art Unit 1631