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 Priority and Status of Claims 1 . This application is a 371 of PCT/US21/49168 9/03/2021, which claims benefit of the provisional application 63075047 9/04/2020. 2 . Amendment including cancelation of claims 13-14, and addition of claims 21-22 in the amendment filed on 11/ 1 0/2025 is acknowledged. Claims 1-12 and 15-22 are pending in the application. O new matter has been found. Since the newly added claims 21-22 are commensurate within the scope of invention, claims 1-12 and 15-22 are prosecuted in the case. Responses to Election/Restriction 3 . Applicant’s election with traverse of claims 1-12 and 15-20 ( n ow are 1-12 and 15-22), in the reply filed on November 10 , 2025 is acknowledged. Election of a compound enzastaurin as a single species is also acknowledged. The traversal is on the ground(s) that a pplicant respectfully requests reconsideration of the Restriction Requirement. It is believed that multiple species can be searched and examined together without undue burden. This is found not persuasive, and the reasons are given infra . Claims 1-12 and 15-2 2 are pending in the application. The scope of the invention of the elected subject matter is as follows. Claims 1-2, 6-1 2, 15-16 and 18 and 20- 22 , are drawn to methods of use using an agent selected from small molecules selected from cobimetinib , trametinib, ruboxistaurin , enzastaurin , or sotrastaurin thereof. The above mentioned claims 3- 5, 17 and 19 having species in the invention which are withdrawn from consideration as being for non-elected subject matter differ materially in structure and composition from the compounds of the elected invention. The withdrawn agents having antibody or fragment, a polypeptide, and a nucleic acid having varying functional groups which differ from those of the elected invention small molecule. This recognized chemical diversity of the functional groups can be seen by the various classification of these functional groups in the CPC classification system, for example the instant antibody or polypeptide is classified in Group subgroup C07 K 14 / 005 . Therefore, again, the agents which are withdrawn from consideration as being for non-elected subject matter differ materially in structure and composition and have been restricted properly. The group set forth in the claims includes both independent and distinct inventions, and patentably distinct compounds (or species) within each invention. However, this application discloses and claims a plurality of patentably distinct inventions far too numerous to list individually. Moreover, each of these inventions contains a plurality of patentably distinct compounds, also far too numerous to list individually. Moreover, the examiner must perform a commercial database search on the subject matter of each group in addition to a paper search, which is quite burdensome to the examiner. Claims 1-2, 6-12, 15-16 and 18 and 20-22 , are drawn to methods of use u sing a small molecule selected from cobimetinib , trametinib, ruboxistaurin , enzastaurin , or sotrastaurin thereof, and are prosecuted in the case. Claims 3-5, 17 and 19 , wherein the agents other than the small molecule are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention. The requirement is still deemed proper and therefore is made FINAL. Claim Rejections - 35 USC § 112 4 . 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 connec ted, 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. 4.1 Claims 1-2, 6-12, 15-16 and 18 and 20-22 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph (pre-A IA), because the specification does not reasonably provide enablement of the instant “ an agent ” without limitation (i.e., no named compounds or formula). 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 the invention commensurate in scope with these claims. ln In re Wands , 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described. They are: 1. the nature of the invention, 2. the state of the prior art, 3. the predictability or Iack thereof in the art, 4. the amount of direction or guidance present, 5. the presence or absence of working examples, 6. the breadth of the claims, 7. the quantity of experimentation needed, and 8. the level of the skill in the art. In the instant case: The nature of the invention The n ature of the invention is a method of use using “ an agent ” without limitation (i.e., no named compounds or formula) , see claims 1, 15 and 18 . The state of the prior art and the predictability or Iack thereof in the art The state of the prior art is Grunicke et al. US 5,578,590 , it discloses a number of protein kinase C inhibitor for treating cancer, see columns 2 and 10. The amount of direction or guidance present and the presence or absence of working examples The only direction or guidance present in the instant specification is the description of a number of agents on pages 12 - 16 of the specification. There is no data present in the instant specification for the “ an agent ” without limitation (i.e., no named compounds or formula) . The breadth of the claims The instant breadth of the rejected claims is broader than the disclosure, specifically, the instant “ an agent ” without limitation (i.e., no named compounds or formula) . The quantity or experimentation needed and the Ievel of skill in the art While the level of the skill in the chemical arts is high, it would require undue experimentation of one of ordinary skill in the art to resolve any “ an agent ” without limitation (i.e., no named compounds or formula) . There is no guidance or working examples present for constitutional any “ an agent ” without limitation (i.e., no named compounds or formula) for the instant invention . Incorp oration of the limitation of “ an agent ” (i.e., claim 21 ) supported by specification into claims 1, 1 5 and 18 respectively would overcome this rejection. 4.2 Claim s 1-2, 6-12, 15-16 and 18 and 20-22 are rejected under 35 U.S.C. 112, first paragraph (pre-A IA), because the specification does not reasonably provide enablement of “preventing a vasculopathy“, see claims 1 and 15 . 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 the invention commensurate in scope with these claims. ln In re Wands , 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described. They are: 1. the nature of the invention, 2. the state of the prior art, 3. the predictability or Iack thereof in the art, 4. the amount of direction or guidance present, 5. the presence or absence of working examples, 6. the breadth of the claims, 7. the quantity of experimentation needed, and 8. the level of the skill in the art. In the instant case: The nature of the invention The nature of the invention of claim s 1-17 and 21-22 is drawn to intent methods of use for preventing “ preventing a vasculopathy ”. The state of the prior art and the predictability or lack thereof in the art The state of the prior art is that the pharmacological art involves screening in vitro and in vivo to determine which compound iloperidone exhibit the desired pharmacological activities (i.e. , what compound iloperidone can treat which specific diseases by what mechanism). There is no absolute predictability even in view of the seemingly high Ievel of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face . The prior art is Grunicke et al.US 5,578,590, it discloses a number of protein kinase C inhibitor for treating cancer, see columns 2 and 10. The instant claimed invention is highly unpredictable as discussed below : It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher , 427 F.2d 833,166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. Applicants are claiming intent methods of use using the instant preventing “ a vasculopathy ” . As such, the specification fails to enable the skilled artisan to use for preventing “ a vasculopathy ” . In addition, there is no established correlation between in vitro or in vivo activity for preventing “ a vasculopathy ” , and those skilled in the art would not accept allegations in the instant specification to be reliable predictors of success, and those skilled in the art would not be able to use the instant compound since there is no description of an actual method “ a vasculopathy ” in a host is prevented . Hence, one of skill in the art is unable to fully predict possible results from the administration of the instant compound due to the unpredictability of preventing “ a vasculopathy ” . The “ a vasculopathy ” is known to have many obstacles that would prevent one of ordinary skill in the art from accepting preventing regimen on its face. The amount of direction or guidance present and the presence or absence of working examples The only direction or guidance present in the instant specification is the description of treating a number of disorders or diseases, see pages 10-16 of the specification. There are no in vitro or in vivo working examples present for preventing “ a vasculopathy ” by the administration of the instant invention. The breadth of the claims The breadth of the claims is methods of use of the instant compounds for treating or preventing “ a vasculopathy ”. The quantity of experimentation needed The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine how “ a vasculopathy ” would be benefited (i.e., treated or prevented ) by the administration of the instant invention and would furthermore then have to determine which of the claimed methods of use would provide preventing “ a vasculopathy ” , if any. The Ievel of the skill in the art The Ievel of skill in the art is high. However, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by successful conclusion'' and ''patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable''. in vitro and in vivo screening to determine which methods of use exhibit the desired pharmacological activity and which would benefit from this activity. Thus, the specification fails to provide sufficient support of the broad use of the pharmaceutical composition of the instant claims for the various diseases or disorders . As a result necessitating one of skill to perform an exhaustive search for which metabolic-related disease s can be treated by what pharmaceutical compound of the instant claims in order to practice the claimed invention. Thus, factors such as "sufficient working examples", "the level of skill in the art" and "predictability", etc. have been demonstrated to be sufficiently lacking in the instantly claimed methods. In view of the breadth of the claim, the chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compound regards to the treatment of the many diseases, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate in scope with the claims. Genentech lnc . v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that “ a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion'' and ''patent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable''. Therefore, in view of the Wands factors and ln re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation, with no assurance of success. This rejection can be overcome by deletion of the limitation “preventing” from claim s 1 and 15 would obviate the rejection. 5 . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status. Claim Rejections - 35 USC § 103 6 . The following is a quotation of 35 U.S.C. 103(a) 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 non-obviousness. This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(f) or (g) prior art under 35 U.S.C. 103(a). Claim 1 -2 , 15, 18 and 21-22 are rejected under 35 U.S.C. 103(a) as being obvious o v er Girach’s US 2008/0096923 and Bowen et al. BioRxiv , May, 8, 2019, pages 1-32. Applicants claim a method of treating or preventing a vasculopathy in a subject, the method comprising: administering an effective amount of an agent, wherein the agent increases the activity or expression of a mitogen-activated protein kinase (MAPK), a protein phosphatase (PP), or a combination thereof, and thereby treating the Vasculopathy , see claim 1. Dependent claims 2 and 21-22 further limit the scope of methods, i.e., the vasculopathy is vascular Ehlers- Danlos Syndrome ( vEDS ) , and the agent is cobimetinib , trametinib, ruboxistaurin , enzastaurin , or sotrastaurin . Applicants claim a method of treating or preventing a vasculopathy in a subject, the method comprising: administering an effective amount of an agent, wherein the agent increases the activity of mitogen-activated protein kinase (MAPK) pathway signaling, wherein the MAPK comprises Map2k6, and thereby treating the vasculopathy , see claim 15. Applicants claim a pharmaceutical composition for the treatment of a vasculopathy, the composition comprising an effective amount an agent, wherein the agent increases the activity or expression of e mitogen-activated protein kinase (MAPK), a protein phosphatase (PP), or a combination thereof, and thereby treating the vasculopathy , see claim 18. Determination of the scope and content of the prior art (MPEP §2141.01) Girach’s ‘923 disclose s methods of use fort treating diabetic microvascular complications (i.e., vasculopathy ) using a composition comprising a therapeutic agent selected from ruboxistaurin and enzastaurin , see columns 14-15. Bowen et al. disclose methods of use for treating vascular Ehlers- Danlos Syndrome ( vEDS ) using a compound selected from cobimetinib , trametinib, ruboxistaurin . Determination of the difference between the prior art and the claims (MPEP §2141.02) The difference between instant claims and Girach’s ‘923 and Bowen et al. i s that the instant claims are embraced within the scope of Girach’s ‘923 and Bowen et al. Girach’s ‘923 and Bowen et al. methods of use and compositions read on instant claims 1 -2 , 15, 18 and 21-22. Finding of prima facie obviousness-rational and motivation (MPEP §2142-2143) One having ordinary skill in the art would find the claims 1-2, 15, 18 and 21-22 prima facie obvious because one would be motivated to employ the compound/ composition and methods of use of Girach’s ‘923 and Bowen et al. to obtain instant invention. Additionally, the discovery of a new property or use, i.e., increas ing the activity or expression of a mitogen-activated protein kinase (MAPK), a protein phosphatase (PP) of a previously known compounds ruboxistaurin , enzastaurin , cobimetinib , and trametinib and methods of use for treating vasculopathy or vascular Ehlers- Danlos Syndrome ( vEDS ) of Girach’s ‘923 and Bowen et al ., even when that property and use are unobvious from the prior art, cannot impart patentability to claims to the known compounds, see In re Spada , 15 USPQ2d 1655 (Fed. Cir. 1990), and MPEP 2112.01. Therefore Girach’s ‘923 and Bowen et al. renders obviousness over the instant invention. The motivation to make the claimed compositions and methods of use derived from the known compound/compositions and methods of use of Girach’s ‘923 and Bowen et al. would possess similar activity to that which is claimed in the reference. Double Patenting 7 . The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the "right to exclude" granted by a patent and to prevent possible harassment by multiple assignees. See In re Goodman , 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi , 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum , 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel , 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington , 418 F.2d 528, 163 USPQ 644 (CCPA 1969). A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b). Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b). Claim s 1 -2, 15, 18 and 21-22 is are rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claim 1 of Dietz et al. US 11,938,135. Applicants claim a method of treating or preventing a vasculopathy in a subject, the method comprising: administering an effective amount of an agent, wherein the agent increases the activity or expression of a mitogen-activated protein kinase (MAPK), a protein phosphatase (PP), or a combination thereof, and thereby treating the Vasculopathy , see claim 1. Dependent claims 2 and 21-22 further limit the scope of methods, i.e., the vasculopathy is vascular Ehlers- Danlos Syndrome ( vEDS ) , and the agent is cobimetinib , trametinib, ruboxistaurin , enzastaurin , or sotrastaurin . Applicants claim a method of treating or preventing a vasculopathy in a subject, the method comprising: administering an effective amount of an agent, wherein the agent increases the activity of mitogen-activated protein kinase (MAPK) pathway signaling, wherein the MAPK comprises Map2k6, and thereby treating the vasculopathy , see claim 15. Applicants claim a pharmaceutical composition for the treatment of a vasculopathy, the composition comprising an effective amount an agent, wherein the agent increases the activity or expression of e mitogen-activated protein kinase (MAPK), a protein phosphatase (PP), or a combination thereof, and thereby treating the vasculopathy , see claim 18. Dietz et al. ‘135 claims a method of treating vascular Ehlers-Danlos Syndrome ( vEDS ) in a subject in need thereof, the method comprising: administering to the subject an effective amount of an agent selected from ruboxistaurin , enzastaurin , sotrastaurin , or a pharmaceutically acceptable salt thereof , see column101. The difference between instant claims and Dietz et al. ‘135 is that the instant claims 1 -2, 15, 18 and 21-22 are embraced directly or indirectly within the scope of Dietz et al. ‘135 . One having ordinary skill in the art would find the claim s 1 -2, 15, 18 and 21-22 prima facie obvious because one would be motivated to employ the methods of use of Dietz et al. ‘135 to obtain instant invention. Additionally, the discovery of a new property or use, i.e., increas ing the activity or expression of a mitogen-activated protein kinase (MAPK), a protein phosphatase (PP) of a previously known compounds ruboxistaurin , enzastaurin , and sotrastaurin and methods of use for treating vasculopathy or vascular Ehlers- Danlos Syndrome ( vEDS ) of Dietz et al. ‘135 even when that property and use are unobvious from the prior art, cannot impart patentability to claims to the known compounds, see In re Spada , 15 USPQ2d 1655 (Fed. Cir. 1990), and MPEP 2112.01. Therefore Dietz et al. ‘135 renders obviousness over the instant invention. The motivation to make the claimed methods of use and compositions derived from the known method of use of Dietz et al. ‘135 would possess similar activity to that which is claimed in the reference. Conclusion Any inquiry concerning this communication or earlier communications from the examiner should be directed to FILLIN "Examiner name" \* MERGEFORMAT REI TSANG SHIAO whose telephone number is FILLIN "Phone number" \* MERGEFORMAT (571)272-0707 . The examiner can normally be reached on FILLIN "Work Schedule?" \* MERGEFORMAT 8:30 am-5:00 pm . Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached on FILLIN "SPE Phone?" \* MERGEFORMAT 571-272- 8394 . The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. /REI TSANG SHIAO/ Rei-tsang Shiao, Ph.D. Primary Examiner, Art Unit 16 91 December 15 , 2025