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 .
Application Status
The preliminary amendment filed on 1/19/2024 is acknowledged. Claims 1-2, 7, 9-11, 13, 17, 19, 25-26, 28, 30-31, 34-36, 43, 45 and 52 are currently pending and under consideration.
Information Disclosure Statement
The listing of references in the PCT international search report is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, “the list ... must be submitted on a separate paper.” Therefore, the references cited in the international search report have not been considered. Applicant is advised that the date of submission of any item of information in the international search report will be the date of submission of the IDS for purposes of determining compliance with the requirements for the IDS with 37 CFR 1.97, including all timing statement requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Objections
Claims 1, 31 and 34 are objected to because of the following informalities:
Claim 1 is objected to because the claims recite the phrase “when present” when defining what the variables encompass. It is suggested that applicants remove this “optional” language so that the definition is in the affirmative.
Claims 31 and 34 recite alternative chemical formulas, but uses the word “and” to separate them. It is suggested that Applicants delete “and” and replace it with “or”.
Appropriate correction is required.
Claim Interpretation
Claim 1 recites A compound having a structure represented by formula selected from:
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. In view of this, the Examiner is interpreting Boron (B) to be substituted with -ORA and -RB, wherein RA and RB are hydrogen or a C1-C8 alkyl.
Claim Rejections - 35 USC § 112
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 31 and 34 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.
Claims 31 and 34 recites compounds containing two -OH groups bonded to the Boron atom such as
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. However, there is insufficient antecedent basis for Boron to be bonded to two -OH groups in the claim, since claim 1, from which claims 31 and 34 depend, appears to recite that RB is either a hydrogen or a C1-C8 alkyl.
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 36, 43, 45 and 52 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The criteria for enablement set out in the In re Wands, MPEP 2164.01(a), considers the following factors:
Breadth of the Claims
The instant claims are directed toward a method of treating a kidney disease or a neurodegenerative disease in a subject in need thereof comprising administering an effective amount of a compound having the formula selected from:
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and
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. The claims further limit the kidney disease to chronic kidney disease, acute kidney injury (AKI), diabetic kidney disease (DKD) and focal segmental glomerulosclerosis. Moreover, the claims further limit the neurodegenerative disease to numerous diseases including, but not limited to, Alzheimer’s disease, Parkinson’s disease and Parkinson’s disease.
Thus, the breadth of the claims is great with regards to the generic recitation of kidney diseases and neurodegenerative diseases, as well as, the number of compounds encompassed by the compounds.
Level of Skill in Art
The level of skill in the art is a clinician or an artisan with a PhD.
Direction and Guidance
The specification, as originally filed, teaches that the invention, in one aspect, relates to compounds and compositions for use in the prevention and treatment of disorders associated with TYRO3 dysfunction such as kidney diseases and neurodegenerative diseases (paragraph 0005). Regarding TYRO3, the specification provides an example of the identification and validation of TRYO3 as a target for Podocyte injury, wherein it was found that TYRO3 expression is highly correlated with the renal function in DKD patients and predictive of the progression in patients with primary glomerular disease which supports a critical role of TYRO3 in human glomerular disease (Example 1). Moreover, the specification teaches the development of TYRO3 agonists, wherein ten compounds were designed, and three pharmacophore groups identified. Specifically, the specification points out the following compounds, all of which contain a 2-5 disubstituted thiazole-4-ol moiety:
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(Example 2). The specification further teaches an assessment of the biologically activities of the 12 compounds on TYRO3 and AKT phosphorylation in podocytes, wherein both C-8 and C-10 induced significantly TYRO3 and AKT phosphorylation, as well as, suppressed NF-kB where the effects of C-10 appeared better than C-8 (Example 3, paragraph 00298). Regarding compound C-10, the specification teaches in vivo studies using C-10 which was found to significantly reduce albuminuria and glomerular injury in these mice with Adriamycin and improved both albuminuria and glomerular injury in diabetic mice (Example 3, paragraphs 00299-00300).
Working Examples
As noted above, the instant specification provides an assessment of the biologically activities of the 12 compounds on TYRO3 and AKT phosphorylation in podocytes, wherein both C-8 and C-10 induced significantly TYRO3 and AKT phosphorylation, as well as, suppressed NF-kB where the effects of C-10 appeared better than C-8 (Example 3, paragraph 00298). Regarding compound C-10, the specification teaches in vivo studies using C-10 which was found to significantly reduce albuminuria and glomerular injury in these mice with Adriamycin and improved both albuminuria and glomerular injury in diabetic mice (Example 3, paragraphs 00299-00300). It is noted that neither compounds C-8 or C-10 are encompassed by the instant claim 1.
Predictability and State of the Prior Art
From a Patent standpoint, there does not appear to be any US Patent applications or US Patents which have issued at the time of filing that specifically target TYPO3 for treating any disease, either by antagonizing or agonizing TYPO3 (search for TYPO3 in abstract or claims). From a non-patent literature perspective, there are numerous articles associating TYPO3 in a variety of diseases. For example, Hsu et al. (Experimental Biology and Medicine 2019; 244:83-99) teaches that although the signal transduction pathways of TYRO3 have not been evaluated in detail, overexpression and activation of TRYO3 receptor kinase have been reported to promote cell proliferation, survival, tumorigenesis, migration, invasion, epithelial-mesenchymal transition or chemoresistance in several human cancers. Today, there is no specific TYRO-3 targeted drug (Abstract). Similar to the results of the specification (Example 1), Zhong et al. (JCI Insight 2018; 3(22):e123482) that TYRO3 plays a critical role in maintaining normal podocyte function and may be a potential new drug target to treat glomerular diseases (Abstract). Lastly, Zhen et al. (PLos ONE, 2012; 7 (6): e39035) looked at the involvement of TYRO3 in amyloidogenic APP processing and B-Amyloid deposition in Alzheimer’s disease models, wherein a significant increase in the number of amyloid plaques in the hippocampus and more plaque-associated clusters were detected in an AD transgenic mouse model accompanied by TYRO3 knockdown (Abstract).
Regarding TYRO3 agonist, the state of the art at the time of filing appears to be silent on TYRO3 agonist useful for treating any disease (google scholar KW: TYRO3 agonist, date limit to 2021).
Regarding the compounds encompassed by claim 1, the compounds of claim 1 appear to be novel. The closest prior art to the claimed compound of claim 1 is considered to be US Patent No 7390670B2 to Akhavan-Tafti et al (2008-06-24) whom teaches a compound having the formula
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which is used as an analytical tool for detection of peroxide or peroxide producing enzymes.
Quantity of Experimentation
In view of the unpredictability of the art/state of the prior art for treating diseases by targeting TYPO3 expression, and the lack of direction in the specification regarding a structure function correlation between the compounds claimed and those specifically tested (C-8 and C-10 which are not claimed), the amount of experimentation required to determine which asserted TYPO3 agonist can treat any and/all kidney diseases or neurodegenerative diseases would be astronomical. For each disease and each TYPO3 agonist, a great deal of experimentation would be required starting with proof-of-concept, and proceeding through all levels of lead identification and optimization. This amounts to invention, not development; it is an undue amount of experimentation.
Note: Two out of the four compounds containing the 2-5 disubstituted thiazole-4-ol moiety were found to be active. As such, it would not appear that the 2-5 disubstituted thiazole-4-ol moiety is critical to the function, nor does the borane moiety since one of the four also contained a borane in addition to C-10.
Conclusion
Claims 31, 34, 36, 43, 45 and 52 are rejected.
Claims 1-2, 7, 9-11, 13, 17, 19, 25-26, 28 and 30 once corrected for some of the objections, would be allowable.
Claims 1-2, 7, 9-11, 13, 17, 19, 25-26, 28, 30-31, 34 are free of the prior art. The closest prior art is considered to be US Patent No 7390670B2 to Akhavan-Tafti et al (2008-06-24) whom teaches a compound having the formula
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which is used as an analytical tool for detection of peroxide or peroxide producing enzymes. The prior art does not teach or suggest removal of one the of methyl moieties to arrive at the claimed compounds.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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BRANDON J. FETTEROLF, PHD
Primary Patent Examiner
Art Unit 1626
/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626
Prosecution Insights