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
Claims 54-68 are currently pending.
Title
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
Claim Objections
Claims 54, 58-65, and 67-68 are objected to because of the following informalities:
Claims 54, 58-61, and 63-64 are objected to because both “hydrogen” and “H” are used to refer to the hydrogen functional group with respect to the variable groups of Formula (I). It is requested that applicant standardized all such terms to either “hydrogen” or “H”.
Claim 62 recites two alternative limitations; however, no “or” appears after the semicolon separating the two limitations.
Claim 65 recites several compounds which are not separated by a semicolon. For example:
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. All such compounds must be followed by appropriate punctuation.
Claims 67-68 recite “a compound” instead of “the compound” of claim 1.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
Claim 68 is 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
The therapeutic and prophylactic treatment of cancer or neoplastic disease mediated by IGF-1R inhibition
The therapeutic treatment of autoimmune disease mediated by IGF-1R inhibition and
The therapeutic and prophylactic treatment of thyroid eye disease (TED),
does not reasonably provide enablement for
The therapeutic and prophylactic treatment of cancer or neoplastic disease not mediated by IGF-1R inhibition
The therapeutic treatment of autoimmune disease not mediated by IGF-1R inhibition
The prophylactic treatment of autoimmune disease
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
In 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 need described. They are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack 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.
The nature of the invention (1) and breadth of the claims (6)
The nature of the invention and breadth of Claim 68 is the treatment of human disease wherein the human disease is a cancer or neoplastic disease, autoimmune disease, or thyroid eye disease wherein treatment comprises both therapeutic and prophylactic treatment comprising administering compounds of Formula (I). Para 65 of the specification provides that the term “treating” refers “to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit.”
The state of the prior art (2) and the predictability or lack thereof in the art (3)
Regarding the capacity of the claimed compounds to treat, therapeutically or preventatively, cancer and neoplastic diseases, Knuppel (Cancer Res; 80(18) September 15, 2020. 4014-4021) teaches “Insulin-like growth factor-I (IGF-I) might be associated with cancer risk…prediagnostic circulating IGF-I concentrations have been shown to be positively associated with colorectal cancer (2), breast cancer (3), and prostate cancer (4) …and there is recent evidence from Mendelian randomization analyses suggesting that these positive associations may be causal” (Page 4014, Introduction). Such results suggest said concentrations of “causal” IGF-I may in fact be targets for prophylactic treatment and the positive association in select cancer similarly suggests utility of IGF-I inhibitors as therapeutic treatments. However, Knuppel further examines different embodiments of cancer to assess the role of IGF-I. Figure 1 of Page 4017
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plots the confidence intervals and hazard ratios of high IGF-1 concentrations against types of cancer. Nearly half have an HR of less than 1 with the upper bounds of the confidence intervals of oral, ovarian, squamous cell carcinoma, and liver cancer lower than 1. Knuppel concludes “The findings suggest that IGF-I is important in the development of several, but perhaps not all, types of cancer” (Page 4020). It remains uncertain what cancers are and are not associated with elevated IGF-1 let alone what cancers might be therapeutically or prophylactically treated with inhibitors thereof.
With respect to autoimmune disease, prophylactic treatment of multiple sclerosis for example is taught by Ghasemi (Cell Journal (Yakhteh), 19, 1, 2017, 1-10.) to be difficult; “the etiology and pathogenesis of MS remains unclear, the present documents illustrate that the cause of MS is multifactorial and include genetic predisposition together with environmental factors” (Abstract). Ghasemi points to genetic and environmental factors that are diverse and not well understood. Prophylactic treatments seem dubious given that even “Conventional therapies for MS…based on the use of anti-inflammatory and immunomodulatory drugs…are not able to stop the destruction of nerve tissue” (Abstract). Further, with respect to IGF-1, Shahbazi (Multiple Sclerosis and Related Disorders 13 (2017) 33–37) reports “According to IGF-1 roles in CNS and our results, this study suggests that low IGF-1 level may be associated with susceptibility to MS” (Abstract). Therefore, the art suggests that inhibition of IGF-1, tantamount to reducing IGF-1 levels and activity thereof, may instead produce a patient who is more susceptible to MS development, a prevalent autoimmune disease. This effect is opposite of the purported use described in Claim 68 and makes prophylactic treatment of autoimmune diseases at least dubious—let alone the prophylactic treatment thereof.
With respect to the single condition listed in Claim 68, TED, Neumann (Eur Thyroid J 2020;9(suppl 1):59–65) describes TED as an orbital manifestation of Grave’s disease in which anti-IGF-1R therapeutics are implicated in an IGF-1 dependent pathway (Abstract). Neumann directly states “insulin-like growth factor 1 (IGF-1) receptor (IGF-1R) has been identified as another important player in the pathogenesis of TED” (Page 60, Left Col). Therefore, the art is clear with respect to the particular condition of TED, that IGF-1 is implicated in the pathogenesis and pathology of TED and that IGF-1 inhibitors may well serve as therapeutic and prophylactic agents in the condition.
The amount of direction or guidance present (4) and the presence or absence of working examples (5)
Applicant describes several select embodiments of Formula (I) which serve as inhibitors of IGF-1R in Examples 1-2 of Pages 176-177 of the specification. It is clear that several of the embodiments are effective inhibitors with low IC50 values. However, applicant does not offer evidence or experimentation or explication of how one of skill in the art would reconcile the claimed therapeutic treatment and prevention of the broad classes of diseases with the above art which suggest that treatment of multiple embodiments of each disease class is not expected, therapeutically or prophylactically.
The quantity of experimentation needed (7)
The quantity of experimentation needed is extremely difficult, novel, and undue experimentation; the ability of IGF-1 inhibitors, or those of Formula (I) specifically, to therapeutically and prophylactically treat the vast genera of cancerous, neoplastic, and autoimmune diseases is nearly impossible to determine and not enabled by the experiments disclosed in the specifications of the application.
Both IGF-1 activity in the pathology and etiology must be determined to evaluate potential therapeutic and prophylactic effects. Such experimentation across the vast genera of disorders must also be evaluated against the vast array of compounds encompassed by Formula (I) of the claims. Such determinations across multiple dimensions comprising vast genera of disease and potentially therapeutic compounds constitute undue experimentation.
The level of the skill in the art (8)
The level of skill in the art is high. One of such skill may recognize the therapeutic and prophylactic potential of IGF-1 inhibition in TED. However, cancers, neoplasms, and autoimmune diseases are vast and complex including diseases of “multifactorial” causes. One of even the highest skill in the art would therefore still not be expected to determine how and which diseases may be prevented or treated with IGF-1 inhibitors—let alone the particular compounds encompassed by Formula (I).
Thus, the specification fails to provide sufficient support for the broad methods of use as described in the instant claims.
Allowable Subject Matter
The closest prior art is found in Fan (US20170056389, 9/27/2024 IDS). Fan teaches
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as Compound 1647 wherein said compound differs from examined Formula (I)
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in that at least:
The R2 substituent (
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) is attached to the Formula (I) X3 position rather than the adjacent carbon.
The R2 substituent (
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) is a cycle attached through an ether group rather than a cycle group as permitted by Formula (I).
The core nitrogen of the bicycle of Formula (I) is instead a CH group in the closest compound of Fan.
Regardless of whether each exchange or modification would be obvious to make alone, it would not be obvious to make all select all three changes to the above compound to render a compound encompassed by examined Formula (I) without impermissible hindsight. The closest prior art compound is too far removed from the genus of Formula (I) and thus Formula (I) and compounds thereof are free of the prior art.
Conclusion
Claims 55-57 and 66 are allowable. Claims 54, 58-65, and 67-68 are objected to. Claim 68 is rejected.
Inquiries
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Richard G. Peckham whose telephone number is (703)756-4621. The examiner can normally be reached 8:30am - 4:30pm EST.
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/RICHARD GRANT PECKHAM/Examiner, Art Unit 1627
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