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 .
Information Disclosure Statement
The information disclosure statement (IDS) dated July 8, 2026 was in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the IDS document was considered and a signed copy of the 1449 form is attached.
Response to Remarks and Amendments
Applicant’s reply filed July 8, 2026 has been entered. All rejections and objections not explicitly maintained herein are withdrawn.
With regard to the rejection of claims 50-51, 54-55 and 57-58 under 35 USC 112(a) for the claims being non-enabled, Applicant contends that the rejection should be withdrawn in view of the amendment to import a list of particular diseases to be treated into rejected claims 50 and 58. However, as pointed out in the original rejection, the scope of “treatment” as claimed also includes prevention/prophylaxis of each of the claimed diseases, which remains non-enabled for the reasons described in the original rejection. The rejected claims should be amended to specify that the method of treatment requires administration to a subject having the claimed diseases, rather than “in need thereof” in order to remove the non-enabled part of the claim scope. The rejection is maintained herein.
With regard to the rejection of claims 1-2, 7, 18, 24, 26-27, 32, 35, 41 and 48-49, the rejection is withdrawn in view of the amendment to import the limitations of claims 15 and 22 into the rejected claims. The prior art fails to teach the limitations of the amended claims.
Status of Claims
Claims 1-2, 7, 15, 22, 24-27, 32, 35, 41, 47-50, 54-55 and 57-58 remain pending and under consideration herein.
Claim Rejections – 35 USC § 112
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 50, 54-55 and 57-58 are 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 treatment of particular diseases in patients already having the particular disease, does not reasonably provide enablement for the treatment and prevention of the entirety of the claimed scope any and all unnamed diseases and disorders (claim 50), which includes all types of cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue."
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 skill in the art
The Nature of the Invention
The nature of the invention is a therapeutic or preventative method for many very broad classifications of diseases, including all various types of cancer.
Further, the instantly claimed “treatment” is defined as the specification as including prophylactic treatment in patients not yet having the claimed disease or disorder. It is further noted that the prophylactic treatment or "prevention" actually means to anticipate or counter in advance, to keep from happening, etc. and there is no disclosure as to how one skilled in the art can reasonably establish the basis and the type of subject to which the instant compounds, compositions, and medicaments can be administered in order to have the "preventative" effect.
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 compounds exhibit the desired pharmacological activities (i.e. what compounds can prevent which specific diseases by what mechanism). There is no absolute predictability even in view of the seemingly high level 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 preventative regimen on its face.
The instantly 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. In the instant case, the instantly claimed invention is highly unpredictable since the claimed compounds encompass many structurally divergent compounds which would not all be expected to have the same activity or utility.
It is well established that "the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity relating to the treatment or prevention of any single disease or disorder is generally considered to be an unpredictable factor.
With specific reference to cancer, Ex parte Kranz, 19 USPQ2d 1216, 1219 notes the “general unpredictability of the field [of] …anti-cancer treatment.” In re Application of Hozumi et al., 226 USPQ 353 notes the “fact that the art of cancer chemotherapy is highly unpredictable”. More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The amount of direction or guidance present and the presence or absence of working examples
The specification teaches that the Tyro-3 inhibition pathway plays a significant role in the initiation and progression of tumors. Regarding the method of use of the compound of Structure (I), the specification describes the in vitro efficacy of a selection of the claimed compounds for the inhibition of Tyro-3, but does not provide any working examples correlating to the actual treatment of any disease.
MPEP 2107.03 states “evidence of pharmacological or other biological activity of a compound will be relevant to an asserted therapeutic use if there is a reasonable correlation between the activity in question and the asserted utility. Cross v. Iizuka, 753 F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985); In re Jolles, 628 F.2d 1322, 206 USPQ 885 (CCPA 1980); Nelson v. Bowler, 626 F.2d 853, 206 USPQ 881 (CCPA 1980).” If correlation is lacking, it cannot be relied upon, Ex parte Powers, 220 USPQ 924; Rey-Bellet and Spiegelberg v. Engelhardt v. Schindler, 181 USPQ 453; Knapp v. Anderson, 177 USPQ 688. Indeed, the correlation must have been established “at the time the tests were performed”, Hoffman v. Klaus, 9 USPQ2d 1657.
Preclinical cancer models, which are principally in vitro cell studies and transplanted tumors (xenografts) have long been understood to have a particularly poor track record and, specifically, do not correlate with actual success in the treatment of cancer. "The fundamental problem in drug discovery for cancer is that the model systems are not predictive at all," says Alan Oliff, executive director for cancer research at Merck Research Laboratories. (Gura, Science 7 November 1997: Vol. 278. no. 5340, pp. 1041 – 1042).
“Preclinical efficacy models in cancer drug discovery … are usually rodent models bearing a transplantable tumor. Yet the vast majority of these investigational drugs fail to meet their pre-specified clinical benefit or efficacy endpoints.” Cancer Drug Design and Discovery Neidle, Stephen, ed. (Elsevier/Academic Press, 2008) page 427.
A direct measure of the low predictive value of preclinical screening for anti-cancer drugs is the low rate of response for Phase 1 clinical trials. Roberts, Jr et al., JAMA 292(17): 2130-2140 (2004), Table 4, shows response rates for the 1999-2002 period ranging from 0.4% to 5.3%; the overall response rate was 3.8%. Percentages this low clearly indicate that the pre-clinical screening as a whole is absolutely not predictive --- even a rate 10 times that high would indicate that the preclinical tests are not reliably predictive. Indeed, the article notes that the response rate to these agents is actually going down over time. Moreover, Roberts, Jr reports that only 44% of the studies were actually published, and since surely studies with unfavorable outcomes are less likely to be published, the actual success rate would be below that 3.8%.
Indeed, oncologists don’t even expect such tests to be reliable predictors. “Cell lines derived under artificial conditions and propagated for decades are not likely to be realistic, or to provide meaningful targets.” Cancer Drug Design and Discovery Neidle, Stephen, ed. (Elsevier/Academic Press, 2008) page 428. The obvious limitations of subcutaneously transplanted xenografts are that they do not reside in the same anatomical site as the corresponding tumor in patients (i.e. are not orthotopic); that 'these generally do not metastasize (metastasis is usually how cancers kill patients); that the blood vessels and stroma are of mouse, not human, origin, and that the cells used are from a homogeneous, not heterogeneous, cell type (real world cancers are heterogeneous). Largely as a result, these systems cannot, for example, model drug resistance. “The most common cause of treatment failure of metastatic cancer is drug resistance… Resistance mechanisms remain an undetermined obstacle to the successful discovery and development of novel targeted therapies. The genomic instability that is a hallmark of cancer contributes to the ability of tumors to develop resistance during therapy (acquired resistance), and the intrapatient heterogeneity of most advanced solid tumors invariably leads to the selection of resistant clones (intrinsic resistance).” Cancer Drug Design and Discovery Neidle, Stephen, ed. (Elsevier/Academic Press, 2008) page 430.
The examiner is not stating that no individual model provides or will ever provide a good correlation with actual efficacy for any specific cancer type. And it is entirely possible that some present or advanced model e.g. an orthotopic or spontaneous metastasis model can or will be shown to correlate with this or that specific cancer. However, given the art-recognition of the fact that that preclinical models in the cancer area do not correlate with actual treatment, the burden is on applicants to show that their particular model has been shown to correlate with whatever particular cancer they wish to claim. In addition, applicants have not established that their actual numbers constitute what would be considered by one of ordinary skill in the art as a positive result.
The breadth of the claims
The claims are extremely broad in that they encompass the treatment and prophylaxis of a broad group of divergent conditions (in fact, an unlimited scope of diseases and disorders), with any compound of the claimed formula, which could reasonably encompass millions of compounds when the breadth of each variable is considered. The claims also recite prevention of the abovementioned diseases and many others.
The level of the skill in the art
The level of skill in the art is high, with the skilled artisan typically possessing an advanced degree such as a Ph.D. or MD. However, due to the nature of the art which, as noted by Das above, is very unpredictable, even compounds that are known to exhibit in vitro activity may not be able to produce adequate immunosuppression and anti-inflammatory actions that lead to amelioration of the disease process in lupus, RA and the entirety of the scope of autoimmune diseases.
Thus, the specification fails to provide sufficient support of the broad use of the compounds of the instant claims for the prevention of these conditions, as a result necessitating one of skill to perform an exhaustive search for which compounds of the instant claims will be useful in order to practice the claimed invention.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine what compounds, out of all compounds, would be effective in treating the entire scope of claimed diseases. Considering that only a relatively small number of compounds was shown to have activity in vitro, and there is no evidence that this data could be extrapolated such that other compounds encompassed by the claimed formula would be expected to have the same activity, in order to practice the claimed invention it could take a lifetime of testing the millions of compounds of the invention for not only promising in vitro activity, but also for use in the prevention of the diseases claimed.
No compound has ever been found to treat or prevent all types of diseases generally or all of the specifically claimed conditions. Since this assertion is contrary to what is known in medicine, proof must be provided that this revolutionary assertion has merits. The existence of such a compound is contrary to our present understanding of modern medicine.
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 claims, the chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compounds, 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 Inc. 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 "[p]atent 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 In 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 to test which agents of the claimed compounds, if any, would prevent any of the claimed diseases, or treat the entire scope of diseases and disorders. It is suggested that in order to overcome this rejection, the claims be limited to the treatment of particular conditions demonstrated or known in the art to correlate to the inhibition of Tyro3 in patients already having the disease.
Claim Rejections – 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 25 and 47 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 25 recites the limitation that the R3a variable is defined as
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. However, the option for R3a to be “heterocyclyl” was deleted by the present amendment. The amended claims include the option for heterocyclyl-alkyl groups, but this requires the point of attachment to be through the alkyl moiety (such as the R3b moiety recited in claim 35, or compound
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in claim 47). Accoridngly, the claimed limitation falls outside the scope of what is encompassed by claim 1. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Conclusion
Claims 1-2, 7, 15, 22, 24, 26-27, 32, 35, 41 and 48-49 are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alicia L. Otton whose telephone number is (571)270-7683. The examiner can normally be reached on Monday - Thursday, 8:00-6:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Mr. Fereydoun Sajjadi can be reached on 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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 extension fee 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 date of this final action.
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699
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