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 1/14/2026 has been received and entered into the case.
Claims 1-8, 10, 16, 18, 22, 25-30, 33-68 have been canceled, claims 69-71 are newly added, and claims 9, 11-15, 17, 19-21, 23-24, 31-32 and 69-71 have been considered on the merits. All arguments have been considered.
The claim rejection under 35 USC 35 U.S.C. 112(a) has been withdrawn due to the instant amendment. It is noted that upon the instant amendment, the previously presented 35 U.S.C. 112(a) rejections have been withdrawn. However, new claim rejections under 35 U.S.C. 112(a) are presented necessitated by the instant amendment.
The claim rejection under 35 USC 112(b) has been withdrawn due to the instant amendment. A new 112b rejection is presented based on the instant amendment.
Claim Rejections - 35 USC § 112 (New Rejection)
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.
Written Description Rejection
Claims 9, 11-15, 17, 19-21, 23-24 and 31-32 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.
The instant claims disclose that the subject is in need of treatment for an ischemic cardiac muscle injury OR at risk of an ischemic cardiac muscle injury. The scope of the subject at risk of an ischemic cardiac muscle injury is broad to not only those
New Matter Rejection
The instant amendment to claim 9 and its dependent claims introduced a limitation to the subject at risk of an ischemic cardiac muscle injury. The instant specification discloses “[i]n several embodiments, piRNA can be administered prophylactically, such as to a subject exhibiting preliminary symptoms or at extremely high risk for an ischemic event.” (para. 64). As disclosed in the cited paragraph, this embodiment is preventative measure. There is no other disclosure with regard to the subject being at risk of ischemic cardiac muscle injury.
The scope of the “at risk of an ischemic cardiac muscle injury” is considered broader than the disclosure of paragraph [0064] as the claimed limitation encompasses any subject and does not limit to a subject with “extremely high risk of ischemic event”.
Thus, the instant amendment introduced new matter to the instant application.
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.
Scope of Enablement Rejection
Claims 9, 11, 13-15, 17, 19-21, 23-24, 31-32 and 69-71 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 hsa-piR-016659 for improving, ameliorating, reducing the severity and/or slowing the progression of ischemic cardiac muscle injury, does not reasonably provide enablement for any other piRNAs than has-piR-016659; the prophylactic or preventative embodiment for a subject at risk of ischemic cardiac muscle injury; or muscle tissue other than cardiac muscle (i.e. skeletal muscle injury or fibrosis) as claimed. 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.
Claim 1 and its dependent claims disclose a method of treating ischemic cardiac muscle injury by administering a therapeutically effective amount of an exosome-derived piRNA to a subject.
Claim 17 and its dependent claims disclose a method of treating any condition requiring muscle tissue repair and/or regeneration, and the condition includes injury to muscle tissue such as muscle tissue fibrosis or ischemic cardiac muscle injury. It is noted that the muscle tissue includes cardiac muscle as well as skeletal muscle.
Claims 12 and 24 are interpreted as the method comprising administering a therapeutically effective amount of hsa-piR-016659. Claim 12 is not included in the instant rejection. It is noted that claim 24 is directed to any injury to any muscle tissue.
The instant specification discloses examples of utilizing piRNAs derived from immortalized cardiosphere-derived cells (ImCDC-EV piRNA) in treating a rat model of myocardial ischemia/reperfusion (Example 2), and the treatment resulted in the increased level of cardiac troponin I (cTnl) compared to scramble RNA-treated animals (Example 2) or decreased amount of monocytes in peripheral blood (Example 3). The therapeutic effect disclosed in the instant specification does not provide any support for the claimed method in preventing or curing the myocardial ischemia/reperfusion injury.
The Examples of the instant specification appear to utilize hsa-piR-016659 to treat a rat model of myocardial ischemia/reperfusion injury, and as indicated above, the examples utilize hsa-piR-016659 for the method of improving or ameliorating ischemic cardiac injury (e.g. myocardial ischemia/reperfusion). However, there is no indication or disclosure that hsa-piR-016659 would sufficiently and necessarily produce any therapeutic efficacy in improving or ameliorating any other condition including muscle fibrosis. Furthermore, there is no showing in the instant specification that other types of piRNAs than hsa-piR-016659 would be able to produce any therapeutic outcome to treat the claimed condition.
While the examples of the instant specification showed improvement in a rat model of myocardial ischemia/perfusion injury by using hsa-piR-016659 but failed to show any other types of piRNAs producing the same effect, the claims of the invention are broadly directed to any piRNAs derived from any exosomes without any evidence or correlation to conclude that other piRNAs would be able to produce the same effect as hsa-piR-016659.
Regarding claim 17 directed to the condition being treated including any condition requiring tissue repair or regeneration of muscle tissue, the scope of the claimed condition is broad to encompass any muscle including cardiac muscle or skeletal muscle, and the condition encompasses any condition, disease or disorder with muscle degeneration. However, there is only a single embodiment and/or working example in the instant specification directed to ischemic cardiac muscle injury as discussed above.
Regarding the method of treating muscle fibrosis as in claims 20-21, as discussed above, the scope of the muscle fibrosis not only includes cardiac muscle fibrosis but also any muscle fibrosis such as skeletal muscle fibrosis. The instant specification does not provide any embodiment with regard to treating skeletal muscle fibrosis. The examples of the instant specification are limited to ischemic cardiac muscle injury or pulmonary fibrosis. There is no working embodiment or example for any skeletal muscle injury being treated with the claimed piRNAs.
The functional aspects of piRNAs are relatively new. According to Sun et al. (2019, ExRNA) and the instant specification, piRNAs are known to function in gene silencing retrotransposons and other genetic elements in germ line cells, and they are found broadly expressed in many kinds of somatic cells and involved in numerous pathological condition. Sun et al. teach that it was found that most of piRNAs exist in the exosome (p.9, 2nd col.). Considering this teaching along with the teaching that there are more than 30,000 piRNAs identified according to Peng et al. (supra), the scope of exosomal piRNAs would be extensive.
There is no evidence that any other exosomal piRNAs than those claimed would be therapeutically effective in treating the claimed condition at the time of filing.
Thus, in the presence of limited showing that hsa-piR-016659 was capable of showing improvement or amelioration in myocardial ischemia/reperfusion, and no additional disclosure of therapeutic efficacy for other species of piRNAs encompassed by the claimed invention, it is highly unpredictable that any other piRNAs would be able to produce the substantially similar, if not identical, effect as shown for hsa-piR-016659.
Regarding the claimed scope of intended purpose, the claims do not particularly disclose the intended purpose of the method being preventative or prophylactic, however, the subject of the claimed method includes those without ischemic cardiac muscle injury or a subject being healthy. This is because the subject is “at risk” of an ischemic cardiac muscle injury and under the broadest reasonable interpretation, the scope would encompass a subject without symptoms or diagnosis of ischemic cardiac muscle injury. This would include a normal subject.
The instant specification fails to provide any guidance or working example to show that the prevention or curing is enabled. In the absence of any embodiment or working example showing the claimed piRNAs would be effectively preventing or curing ischemic cardiac injury, cardiac fibrosis, myocardial infarction, or any condition requiring a tissue repair and/or regeneration, it is highly unexpected that the claimed method would produce the claimed prevention and/or cure for the cardiac muscle injury or any tissue injury, particularly when it is well known in the art that ischemic cardiac muscle injury such as myocardial infarction or any tissue fibrosis including cardiac fibrosis and pulmonary fibrosis is not preventable or curable (see Ojha et al. 2023; Cleveland Clinic 2025). Without any evidence or guidance, and the unpredictable nature of the method, undue experimentations are required.
M.P.E.P. § 2164.03 reads, “The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The ‘amount of guidance or direction’ refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling. See, e.g., Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1326 (Fed. Cir. 2004) (“In applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims. In cases involving unpredictable factors, such as most chemical reactions and physiological activity, more may be required.”).”
Based on the limited disclosure in the specification, highly unpredictable nature of the claimed method, and lack of guidance and working embodiment commensurate with the entire scope of the claimed invention, it is considered that undue experimentations would be required to make/use the claimed invention.
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 9, 11-15, 17, 19-21, 23-24, 31-32 and 69-71 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 9 discloses that the subject being administered with the piRNA is at risk of an ischemic cardiac muscle injury. The term “at risk” would be interpreted such that the subject is prophylactically or preventatively administered with the piRNA, and thus, the scope of the subject is any one with or without any symptoms indicative to the ischemic cardiac event. However, the intended purpose of the claimed invention is directed to “improving, ameliorating, reducing the severity of, preventing, and/or slowing the progression of ischemic cardiac muscle injury. The term “preventing” is understood as “preventing the progression of ischemic cardiac muscle injury”. Thus, the claimed method requires the subject having ischemic cardiac injury according to the intended purpose, but the claim also includes the subject without ischemic cardiac muscle injury, e.g. healthy subject, as a preventative method. It is not clear whether the method includes preventative or prophylactic treatment to prevent any subject from developing ischemic cardiac muscle injury. Clarification is required.
Claim 71 discloses the term “at extremely high risk”. The terms “extremely” and “high” are considered as relative terms which render the claim indefinite. The term “extremely high” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Response to Arguments
Applicant’s arguments with respect to the 112 rejection(s) have been fully considered and are persuasive for portion of the issues raised in the previous OA. Therefore, the portion of the rejection has been withdrawn. However, upon further consideration based on the instant amendment, a new ground(s) of rejection is made as presented above.
Regarding the 35 U.S.C. 112(a) rejections, applicant argued that the present application shows that in some non-limiting embodiments, injury to cardiac muscle due to cardiac ischemia followed by reperfusion is significantly reduced when RNA having the nucleotide sequence of a CDC-derived exosomal piRNA such as has-piR-016659 was administered. Applicant alleged that extracellular vesicles obtained from immortalized CDCs (and that are enriched in piRNA, including hsa-piR-016659) have an effect on the same target cell types (e.g., monocytes and macrophages) as does hsa-piR-016659, e.g. Examples 3, 4.
The examples of the instant specification showed that both imCDC-EV and imCDC-EV piRNA (hsa_piR_016659) showed that imCDC-EV as well as hsa-piR-016659 provided effective outcome in treating myocardial ischemia/reperfusion injury. These data, however, do not indicate or suggest any single species of piRNA present in the EVs is capable of producing the same effect as the EVs or hsa-piR-016659. There is no other disclosure for the rest of the piRNA species or any piRNA from CDC for ischemic cardiac muscle injury of claim 1 or any other conditions encompassed by the genus of muscle tissue injury of claim 17. There is no showing for the effective treatment of hsa-piR-011659 for skeletal muscle injury or muscle fibrosis or the EVs from CDC for that matter. Thus, it is the Examiner’s position that the specification fails to provide sufficient written description to support the entire genus of the claimed invention.
Regarding the scope of enablement rejection, it is noted that the rejection is mainly focused on such that there is no enabling embodiment to consider that any other species of piRNAs present in the EVs from CDC would be able to carry out the same effect as the EVs or hsa-piR-016659 in producing the claimed therapeutic effect in ischemic cardiac muscle injury. Furthermore, there is no indication that the CDC-EVs can product therapeutic efficacy in any muscle injury or muscle fibrosis, let alone hsa-piR-016659. As discussed in the claim rejection, there is no information known in the art at the time of filing that any single species of piRNA is capable of carrying out the claimed effect. The instant specification provides data supporting that hsa-piR-016659 has the same effect as the EVs in treating cardiac ischemia/reperfusion injury. There is no basis to believe that any other piRNAs would have the same effect as hsa-piR-016659, and thus, it is highly unpredictable that any additional piRNAs from CDC-EVs would be effective in the treatment of the claimed condition, hence this necessitates undue experimentations.
It is noted that the instant amendment raised additional issues under 35 U.S.C. 112(a) as well as 112(b) as discussed in the claim rejection above.
Conclusion
No claims are allowed.
Claims 9, 11-15, 17, 19-21, 23-24, 31-32 and 69-71 are free of prior art.
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