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 .
Priority
The instant application is a 371 of PCT/US2022/019759, filed March 10, 2021, which claims the benefit of an effective US filing date from provisional application 63/159,063, filed March 10, 2021.
Information Disclosure Statement
No information disclosure statements (IDS) has been filed in the instant application. Applicants are reminded of their duty to disclose all information known to them to be material to patentability as defined in 37 CFR 1.56.
Election/Restrictions
Applicant’s election of Group I (compounds of Formula (I)), in the reply filed on January 26, 2026 is acknowledged. Further, Applicant’s election of Compound 302
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in the same reply is also acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Upon further consideration, it was found that no prior art anticipates or renders obvious the formula I, as presently amended, which is the technical feature of the instant claims. Thus, the amended claims are found to possess unity of invention and the restriction requirement made under lack of unity practice is withdrawn. In view of the withdrawal of the restriction requirement as to the rejoined inventions, applicant(s) are advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application. Once the restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Status of the Claims
Currently, claims 41-86 are pending in the instant application and under consideration herein.
Claim Rejections - 35 USC § 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 85-86 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification does not reasonably provide enablement for the treatment of any and all diseases (claim 85, which places no limitation on the scope of disease or condition to be treated), or for the full scope of “treatment” which includes prophylaxis, prevention, or delaying the onset of the disease or condition (see SPEC paragraph [0063]), such as rheumatoid arthritis (RA), solid tumors, or hematological tumors (which, without limitation, include all cancerous forms of said tumors). 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 a general rule, enablement must be commensurate with the scope of claim language. MPEP 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed most recently in Liebel-Flarsheim Co. v. Medrad, Inc. 481 F.3d 1371, 82 USPQ2d 1113; Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008).
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 rheumatoid arthritis (RA) and all solid and hematological tumors.
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. Unpredictability in treating or preventing the claimed diseases is established by the following:
Das, U.N. (Journal of Inflammation Research, 2010:3, pages 143 –170) reviews strategies for the treatment and management of rheumatoid arthritis, a chronic inflammatory condition, based on molecular signatures of acute and chronic inflammation (Title, abstract). Das discloses that the current strategy of management includes administration of nonsteroidal anti-inflammatory drugs and immunosuppressive drugs such as corticosteroids (Abstract). Das discloses (page 144, right column, 1st paragraph)
“the response of patients with lupus and rheumatoid arthritis is variable. Some respond, others may not respond, and some may show only a partial response to the same therapeutic measures. This type of differential response is at times baffling and suggest the involvement of various organs and tissues due to the underlying inflammatory process is varied, and the degree of involvement may differ in both time and extent and, more importantly, is unpredictable. It is also possible that continued inflammatory events seen in lupus, rheumatoid arthritis (RA) and other rheumatological conditions, could be due to failure of the resolution of inflammation. Thus, the balance between inflammation and resolution is disturbed more in favor of proinflammatory events and/or failure of resolution molecules to be produces at the most appropriate time, leading to non-resolution of inflammation. In other words even after the inciting agent responsible for the initiation of inflammation is removed, inappropriate inflammation continues simply because resolution failed to occur. This leads to delay in the healing/repair process and so tissue/organ damage continues. This may explain why target organ damage continues even when these patients are continuing to take antiinflammatory and immunosuppressive medicines. In view of this, it is imperative that administration of proresolution-inducing agents is needed to obtain full remission and restore normal physiological function of the target tissues/organs in these diseases.
Das discloses lipoxins as an example of one of several pro-resolution-inducing molecules and states:
“Hence, understanding the interactions(s) between proinflammatory and anti-inflammatory and pro-resolution molecules is important to devise newer therapeutic strategies in several inflammatory conditions.”
Das concludes by stating (page 165, 1st and 2nd paragraphs)
“Although there have been significant advances in the management of autoimmune diseases by the use of these drugs, especially biologics, their actions are often unpredictable: Not all patients respond adequately to these therapeutic approaches…Hence….newer therapeutic approaches are needed.
It is possible that GIK, EP, lipid-enriched albumin, VNS, PUFA’s and their products LXs, resolvins, protectins and ghrelin altogether may not be able to produce adequate immunosuppression and anti-inflammatory actions that lead to amelioration of the disease process in lupus, RA and other autoimmune diseases.
It is recommended that some of these suggested approaches could be performed in combination with the currently available therapeutic drugs. For example, GIK regimen, ethylpyruvate, lipid-enriched albumin, VNS, LXs, resolvins, protectins and their synthetic analogs, and ghrelin could be tried in combination with nonsteroidal anti-inflammatory compounds, chloroquine (hydroxychloroquine), corticosteroids (oral or parenteral), d-penicillamine, sulfasalazine, methotrexate, anti-TNF antibodies, and immunosuppressive drugs (such as cyclosporine, cyclophosphamide, and azathioprine).
Another option that could be investigated is the use of anti-TNF-α and other biologics in combination (as a complex or separately) with EP, ghrelin, PUFAs, LXs, resolvins and protectins, and insulin and be used as parenteral infusion.
All these permutations and combinations need to be tried both in the animal models of various autoimmune diseases and other inflammatory conditions and in the clinic before knowing which therapeutic approach is of significant benefit to these patients. With such an approach, one can measure various plasma tissue factors, as shown in Table 1, to determine the effectiveness of the therapeutic approach employed”.
Accordingly, the disclosure of Das casts doubt on whether administration of any single anti-inflammatory agent, or any combination of potential anti-inflammatory agents will predictably be effective in treating diseases characterized by chronic inflammation or an autoimmune response. As noted above, Das cautions that, in view of said unpredictability in the art, all permutations and combinations of potential therapeutic agents need to be tried both in the animal models of various autoimmune diseases and other inflammatory conditions and in the clinic before knowing which therapeutic approach is of significant benefit to these patients.
With respect to the claimed autoimmune diseases, these processes are too divergent and can require different methods of treatment depending on the particular disease and the underlying mechanism. Examples of auto-immune diseases include, but are certainly not limited to: lupus, nervous system disorders such as multiple sclerosis, and rheumatoid arthritis. This broad list of diseases and conditions each has a different cause and, for the majority of the list, a different treatment. There is not one class of compounds, let alone one compound, which can treat and much less prevent (or prevent recurrence of) all of these diseases or conditions.
Although the state of the prior art with regards to each and every disease encompassed by the claims cannot be discussed, the following are meant to serve as examples. It is known in the art that the treatment and development of new treatments for autoimmune diseases such as multiple sclerosis is notoriously difficult. Although the state of the prior art with regards to each and every disease encompassed by the claims cannot be discussed, the previous paragraphs are meant to serve as examples.
The amount of direction or guidance present and the presence or absence of working examples
A disclosure should contain representative examples which provide reasonable assurance to one skilled in the art that the compounds which fall within the scope of a claim will possess the alleged activity. The only direction or guidance present in the specification is the listing of diseases Applicant considers treatable and in vitro data showing the ability of exemplified compounds of the invention to inhibit the claimed integrin receptors. Thus, the issue becomes whether the skilled artisan would conclude that data providing evidence that the exemplified compounds are effective (to vastly differing degrees) to inhibit particular receptors is sufficient to extrapolate to the use of millions of different compounds, having substantially different structures, for the prevention and treatment of entire classes of diseases which have been notoriously difficult to treat and not possible to prevent. Receptor activity is generally unpredictable and a highly structure specific area, and the data provided is insufficient for one of ordinary skill in the art to extrapolate.
The disclosure does not provide how this in vitro data correlates to the prevention of the assorted diseases claimed. See MPEP 2164.02 (“The issue of “correlation” is related to the issue of the presence or absence of working examples. “Correlation” as used herein refers to the relationship between in vitro … assays and a disclosed or a claimed method of use. An in vitro … example, in the specification, in effect, constitutes a “working example” if that example “correlates with a disclosed or claimed method invention. If there is no correlation, then the examples do not constitute “working examples.” … For a claimed genus, representative examples together with a statement applicable to the genus as a whole will ordinarily be sufficient if one skilled in the art … would expect the claimed genus could be used in the manner without undue experimentation”). While Applicants do indeed make various statements in the specification that their claimed compounds will effectively treat or prevent the genus of claimed diseases, such is not supported by conclusive examples.
The breadth of the claims
The claims are extremely broad in that they encompass the treatment and prevention of a broad group of divergent conditions, 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 and cure of the diseases claimed.
No compound has ever been found to treat, prevent or cure all types of autoimmune diseases, inflammatory diseases, or cancers 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.
In the present case, based on the expected activity of compounds of formula (I) as integrin inhibitors as disclosed in the specification, a method of treating the symptoms of particular diseases as identified above which would be reasonably expected to be treatable with the described mechanism is enabled. This does not include the prophylaxis, prevention, or delaying the onset of any of the claimed diseases. This also does not include the treatment of any and all unlimited diseases as recited in claim 85. Such a need equates to a burden of undue experimentation to practice the invention commensurate with the full scope of the claims.
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 with no assurance or reasonable expectation of success.
Relevant Prior Art Documents
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure: WO 2005/082889 represents the closest prior art to compounds of Formula (Ia). Particular note is made of example 8, which is structurally identical to the instant formula except for the X-Y group, which requires two carbon atoms linked by a single bond in the prior art. The present claim amendment eliminates this definition from the instant scope and the prior art does not provide the requisite motivation to change this portion of the structure to one of the X-Y groups within the instantly claimed scope. Since there is no teaching or suggestion in the prior art which would have led a person of ordinary skill towards the instantly claimed compounds, the compounds of Formula (Ia) are considered allowable.
Conclusion
Claims 41-84 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 at 571-272-3311. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699