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
Status of 17/768,344
Claims 49-55 and 58-68 are currently pending.
Priority
Instant application 17/768,344, filed 4/12/2022, claims priority as follows:
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The effective filing date of a claimed invention is determined on a claim-by-claim basis. See MPEP § 2152.01.
The priority document U.S. Provisional Application No. 62/915,932 fails to provide support under 35 U.S.C. 112 for limitations present in claims 53, 55, 58, 61, 64-65, and 68. Specifically, the limitations tubastatin, SB431542, K02288, a PAR1 inhibitor, and an inhibitor of a lymphatic tube regression are not present in the provisional application. Therefore, claims 53, 55, 58, 61, 64-65, and 68 are not entitled to an effective filing date of 10/16/2019.
The priority document PCT/US2020/056077 contains support for the limitations of claims 53, 55, 58, 61, 64-65, and 68. Therefore, claims 53, 55, 58, 61, 64-65, and 68 are entitled to the effective filing date of 10/16/2020.
Information Disclosure Statement
All references from the IDS submitted on 4/12/2022 have been considered unless marked with a strikethrough.
Response to Applicants Amendments/Arguments
The amendment filed 7/2/2026 has been entered. Claims 49 and 63 have been amended.
In the Non-Final dated 5/29/2026, the drawings were objected to for being pixelated and illegible. In response, Applicant has submitted replacement drawings. However, the drawings remain pixelated and illegible, and the objection is maintained.
The abstract was objected to in the Non-Final dated 5/29/2026 for a minor grammatical informality. In response, Applicant has corrected the informality, which overcomes the objection. Thus, the objection is withdrawn.
Claim 49 was objected to for a minor informality in the Non-Final dated 5/29/2026. Applicant has corrected the informality in response, which overcomes the objection. The objection is withdrawn.
In the Non-Final dated 5/29/2026, claims 49 and 63 were rejected under 35 U.S.C. 112(b). In response, Applicant has amended claim 49 to recite, “wound repair”, and has struck through the terms, “about”, in claim 63, which overcomes the rejection. Thus, the rejection is withdrawn.
Claims 49-51, 58, and 63 were rejected in the Non-Final dated 5/29/2026 under 35 U.S.C. 103. In response, Applicant argues that the cited combination fails to disclose each and every element of the claims, and thus the Office has failed to establish a prima facie vase of obviousness. Further, Applicant argues the use of impermissible hindsight, and that the 103 rejection of the Non-Final dated 5/29/2026 fails to provide a clear articulation of the reasons why the claimed invention would have been obvious and explicit analysis to support that conclusion. The rejections under 35 U.S.C. 103 cannot be supported with “mere conclusory statements” and that there must be “some articulated reasoning with some rational underpinning”.
With respect to Applicants arguments that the cited combination fails to disclose each and every element of the claims and that none of the references disclose a method of inhibiting capillary tube regression, the arguments have been considered, but are unpersuasive according to MPEP § 2112. Though the mechanism of action of inhibition of capillary tube regression may not have been fully elucidated at the time of publication of Russo, Chanoit, Legos, Leng, and Itoh, the references do teach each individual compound of the instant combination administered in a successful treatment of ischemia. Stated differently, an argument can be made that the inhibition of capillary tube regression was occurring in Russo, Chanoit, Legos, Leng, and Itoh, though not explicitly stated, because the compounds of the instant combination were administered in successful treatments of ischemia. Regarding the “confirming the presence of the capillary tube regression in the patient” limitation of instant claim 49, the broadest reasonable interpretation of the limitation includes the definition in claim 50, which recites measuring a level of at least one pro-regressive growth factor or cytokine and comparing the measured level to a normal control wherein an increase in the measured level of the at least one pro-regressive growth factor or cytokine as compared to the normal control confirms the presence of the capillary tube regression. This is taught by the reference Ridker in the Non-Final dated 5/29/2026.
In response to Applicant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the Applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Additionally, Applicant argues that there is no clear articulation of reasons why the claimed invention would have been obvious. This argument has been considered, but is not persuasive because even though Applicants chose the path of screening thousands of compounds, the compounds selected in the final combination are all known in the art to individually treat ischemia. A skilled artisan would be motivated to combine the individual ingredients to improve methods of treating ischemia and would reasonably expect success. Thus, the rejection is maintained. The Examiner notes this rejection can be overcome by the submission of unexpected or synergistic results.
Election/Restriction
Applicant’s election of Group I, claims 49-63, drawn to methods of treating diseases with inhibitors of capillary tube regression, without traverse, in the reply filed 3/20/2025 is acknowledged. Applicant’s election of ischemia as the species of disease to treat, and the combination of forskolin, IBMX, SB239063, and TCS-HDAC6 as the species of inhibitor composition, without traverse, in the reply filed 3/20/2025 is also acknowledged. For the purpose of clarity, the Examiner notes the above compounds are known in the art and have the following Cas No.’s: forskolin has a Cas No. of 66575-29-9, IBMX has a Cas No. of 28822-58-4, SB239063 has a Cas No. of 193551-21-2, and TCS-HDAC6 has a Cas No. of 956154-63-5.
Examination will begin with the elected species. In accordance with MPEP § 803.02, if upon examination of the elected species, no prior art is found that would anticipate or render obvious the instant invention based on the elected species, the search of the Markush-type claim will be extended. If prior art is then found that anticipates or renders obvious the non- elected species, the Markush-type claim will be rejected. It should be noted that the prior art search will not be extended unnecessarily to cover all non-elected species. Should Applicant overcome the rejection by amending the claim, the amended claim will be examined again. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. In the event prior art is found during further examination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final.
In the Non-Final dated 5/5/2025, the elected species were searched and prior art was identified. During the search, additional prior art was identified and the scope was expanded to where the inhibitor of capillary tube regression is a small molecule pharmacologic agent and the treatment of other diseases. The initial rejection was overcome; however, a new 103 rejection has been identified. The scope of the claims has not been fully searched in accordance with Markush search practice. Thus, claims 49-51, 58, and 63 are the current subject matter in this Office Action. Claims 52-55, 59-62, and 64-68 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species and/or group, there being no allowable generic or linking claim.
Claim Interpretation
Claim 49 recites the phrase, “therapeutically effective amount” in reference to the amount of capillary tube regression inhibitor administered to the patient. The specification does not define the term “therapeutically effective amount”, but does state that the pharmacologic agents can be administered at a dose at about 1 mg/kg to 200 mg/kg (page 20, lines 15-17). No examples are provided in the specification wherein a capillary tube regression inhibitor is administered to a patient to treat a disease. Accordingly, any dose within the range of 1 mg/kg to 200 mg/kg is considered to meet the dose limitation described as a “therapeutically effective amount”.
MAINTAINED OBJECTIONS AND REJECTIONS
Objection to Drawings
New corrected drawings in compliance with 37 CFR 1.121(d) are required in this application because Figures 1-12, 14-15, 17, 19 are not able to be interpreted as they are pixelated and illegible. Applicant is advised to employ the services of a competent patent draftsperson outside the Office, as the U.S. Patent and Trademark Office no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 49-51, 58, and 63 are rejected under 35 U.S.C. 103 as being unpatentable over Ridker (Ridker, P. M. et. al. Circulation. 2000, 101(18), 2149-2153.) in view of Russo (Russo, R. et. al., Molecular Vision. 2015, 21, 718-729), Chanoit (Chanoit, G. et. al. Cardiovasc. Drugs. Ther. 2011, 25, 299-306), Legos (Legos, J. J. et. al. Brain Research. 2001, 70-77), and Leng (Leng, Y. et. al. Oxid. Med. Cell. Longev. 2018, 1-15) in combination with Itoh (Itoh, Y. et. al. J. Med. Chem. 2007, 50, 5425-5438).
Determining the scope and contents of the prior art
The reference Ridker teaches that levels of tumor necrosis factor-α (TNF-α) increase with acute ischemia (abstract) and that there is an increased risk of repeat coronary events with the elevated levels of TNF-α after myocardial ischemia. Specifically, Ridker teaches Table 2 (page 6):
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Which demonstrates the increase in the plasma concentration of TNF-α in patients with recurring myocardial ischemias compared to the control group. This helps teach the limitations of instant claims 49-51 that are drawn to confirming the presence of the capillary tube regression in the patient by measuring a level of at least one cytokine and comparing the measured level to a normal level, the cytokine being TNF-α. According to Applicants disclosure, this confirms the presence of the capillary tube regression in the patient, though not explicitly stated in Ridker.
The references Russo, Chanoit, Legos, and Leng in combination with Itoh, teach the individual compounds of the composition as compounds able to treat ischemia.
The reference Russo teaches forskolin as a treatment of ischemia after the administration of forskolin was found to reduce cell loss post-ischemia (page 721, Figure 1A), and with respect to claim 63, further teaches a dosage of 0.6-6 nmol/eye (page 719, last paragraph).
The reference Chanoit teaches IBMX as a treatment of ischemia by administration of IBMX at the onset of reperfusion. IBMX significantly increased cell viability, indicating IBMX can protect cardiac cells from ischemia/reperfusion injury (page 302, left column). Further, Chanoit teaches the ischemia cells were exposed to a 10 μM solution of IBMX (page 301, first paragraph).
Legos teaches SB239063 as a treatment of ischemia by oral administration resulting in a lessening of the infarct volume in forebrain tissue (page 73, Figure 2), and with respect to claim 63, further teaches a dose range for oral SB 239063 administered to animals of 5, 15, 30, and 60 mg/kg (page 72, first paragraph).
Finally, the reference Leng teaches that HDAC6 inhibitors treat ischemia after the administration of tubastatin A increased cell viability post-ischemia (Page 10, Figure 6g), and with respect to claim 63, further teaches the dosage of the HDAC6 inhibitor as 10 mg/kg (page 2, section 2.3). Additional reference Itoh discloses elected compound TCS-HDAC6 as compound 20b (page 5428, Figure 1) and as an HDAC6 inhibitor (page 5428, Figure 2), indicating the compound has the same mechanism as tubastatin A of Leng.
Ascertaining the differences between the prior art and the claims at issue
The reference Ridker fails to teach the inhibitor of capillary tube regression composition and thus the administration of the inhibitor to the patient. The references Russo, Chanoit, Legos, and Leng in combination with Itoh, fail to teach the combination of the individual compounds in methods of treating ischemia and the explicit conformation of capillary tube regression in a patient.
Resolving the level of ordinary skill in the pertinent art
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of methods of inhibiting capillary tube regression to treat diseases. An artisan possess the technical knowledge necessary to make adjustments to the methods of treatment to enhance their effectiveness. Said artisan has also reviewed the problems in the art as regards to methods of inhibiting capillary tube regression to treat diseases and understands the solutions that are widely known in the art.
Considering objective evidence present in the application indicating obviousness or nonobviousness
Applying KSR prong (A), it would have been prima facie obvious to combine the teachings of Ridker, Russo, Chanoit, Legos, and Leng in combination with Itoh to arrive at the method of inhibiting capillary tube regression to treat a disease, such as ischemia, with the composition of forskolin, IBMX, SB239063, and TCS-HDAC6. A skilled artisan would have reasonably predicted that the methods and ingredients taught by the individual references could be combined because the references above teach that each individual compound is suitable for treating ischemia. Further, a skilled artisan would have been motivated before the effective filing date to combine the individual compounds of Russo, Chanoit, Legos, and Leng in combination with Itoh to identify additional methods of ischemia treatment. Since this modification of the prior art represents nothing more than the predictable use of prior art elements according to their established functions, a prima facie case of obviousness exists.
Regarding claim 63, it would have been prima facie obvious to one having ordinary skill in the art to arrive at the concentration of the inhibitor of capillary tube regression consisting of forskolin, IBMX, SB239063, and TCS-HDAC6 recited in the instant claims because it is considered well within the capabilities of one of ordinary skill in the art to optimize the concentrations of individual ingredients of the formulation to provide optimal capillary regression inhibition. The concentration of each individual ingredient in the formulation is a result effective parameter that will affect the physical properties of the final composition. The amount of an ingredient in a composition is clearly a result effective parameter that a person of ordinary skill would routinely optimize. Optimization of parameters is a routine practice that would have been obvious for a person of ordinary skill in the art to employ and reasonably would expect success. Moreover, the ratios of forskolin, IBMX, SB239063, and TCS-HDAC6, disclosed by the prior art above, provide a range of workable conditions and it would have been customary for an artisan of ordinary skill to determine the optimal ratios of forskolin, IBMX, SB239063, and TCS-HDAC6 to best achieve the desired result. Furthermore, absent any evidence demonstrating a patentable difference between the composition and the criticality of the claimed amounts, the determination of the optimum workable range(s) given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. See MPEP § 2144.05 [R-2](II) (A) and In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) “[W]here the general conditions of the claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Close Prior Art Not Rejected Under 35 U.S.C. 102 or 103
The reference Koller (Koller, G. M. et. al. Arterioscler. Thromb. Vasc. Biol. 2020, 40, 365-377) discloses proinflammatory mediators that regulate capillary tube regression, and pharmacological inhibitors thereof (abstract). Specifically, Koller discloses the small-molecule compositions FIST, which consists of forskolin, IBMX, SB239063, and tubacin, and FISTB, which consists of the four former compounds as well as a fifth drug, SB415286 (page 370). FIST and FISTB drug combinations completely rescued the pro-regressive influence of the proinflammatory mediators found to regulate capillary tube regression (page 371, Figure 4).
Though this reference was first published 12/19/2019, which is before the effective filing date 10/16/2020 of claims 53, 55, 58, 61, 64-65, and 68, the disclosure was made by the joint inventors of the instant application and thus falls under the 35 U.S.C. 102(b)(1) exception.
Conclusion
Claims 49-51, 58, and 63 are rejected. Claims 52-55, 59-62, and 64-68 are withdrawn.
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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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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