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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/5/2025 has been entered.
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 10/28/2025 has been entered. Claims 49 and 58 have been amended. No claims have been added or cancelled.
In the Final dated 9/5/2025, claims 49-51, 58, were 63 are rejected under 35 U.S.C. 112(a). In response, Applicant argues that the disclosure identifies pro-regressive factors enumerated in claim 51, and also indicates that multiple distinct factors and pathways are involved in capillary tube regression and thus treatment is not only limited to MMP-1 and MMP-10 inhibitors. Additionally, Applicant has identified the scope of diseases Applicant claims to be able to be treated by the capillary inhibitor composition of the instant claims, and amended claim 49 to further reflect that. Applicants arguments have been considered, and are persuasive because Applicant has identified pro-regressive factors and cytokines measured in addition to narrowing the scope of diseases to ensure Applicants had possession of the knowledge of the invention at the time of filing. This overcomes the rejection, and the rejection is withdrawn.
Claim 49 was objected to in the Final dated 10/28/2025 for a minor grammatical formality. In response, Applicant has amended the claim, which overcomes the objection. Thus, the objection is withdrawn.
In the Final dated 10/28/2025, claims 49-51, 58, and 63 were rejected under 35 U.S.C. 112(b). In response, Applicant has amended claim 49 to clarify “TCS-HDAC6” and amended claim 58 to correct the lack of antecedent basis with respect to the histone deacetylase 6 inhibitor, which overcomes the rejection. Thus, the rejections are withdrawn.
However, additional rejections were identified and are the subject of this office action.
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.
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.
Objection to the Abstract
The abstract of the disclosure is objected to for a minor informality. Specifically, the end of the last sentence reads, “viral infection (e.g., influenza or SARS-CoV-2), bacterial infection”, and fails to use a coordinating conjunction in the list. Appropriate correction is required.
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”.
Claim Objections
Claim 49 is rejected to for a minor informality. Claim 49 recites, “confirming presence”, but should read “confirming the presence”. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 49-51, 58, and 63 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 49 recites the limitation, “wound repair response” in reference to a disease having capillary tube regression as a pathogenic factor. The disease is not defined by the claim or specification, and one of ordinary skill in the art would not reasonably be apprised of the scope of the disease. Thus, the scope of the diseases having capillary tube regression as a pathogenic factor is rendered indefinite by the limitation “wound repair response”. Dependent claims 50-51, 58, and 63 do not resolve the issue by claiming a specific disease and are thus also rejected. Appropriate correction is required.
Claim 63 recites the limitation, “about”, in reference to the amount of capillary tube regression inhibitor administered to the patient. The term “about” is a relative term which renders the claim indefinite. The term “about” 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. Thus, the scope of dosages is rendered indefinite by the term “about”. In the interest of compact prosecution, the term “about” is currently being interpreted mean ±10% of the subsequent value modified by the term. Appropriate correction is required.
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.
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/K.N.H./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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