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 35 US 371 National Stage filing of international application PCT/GB2022/51042, filed April 25, 2022, which claims priority under 35 USC 119(a)-(d) from Applications GB2117433.9 and GB2105942.3, filed December 2, 2021 and April 26, 2021, respectively.
Information Disclosure Statements
The information disclosure statements (IDS) dated October 19, 2023 and January 9, 2024 were in compliance with the provisions of 37 CFR 1.97 and 1.98. Accordingly, the IDS documents were considered and signed copies of the 1449 forms are attached.
Election/Restrictions
Applicant’s election with traverse of the invention of the species of compound 11,
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in the reply filed July 24, 2026 is acknowledged. The elected species reads on claims 1-3, 14-17, 20-21, 23-27, 29, 43 and 46. Applicant’s traversal (in the original response filed March 6) was that formulae (I.1) and (Ii) each fully fall within the scope of formula (I). This traversal does not apply to the requirement as set forth in the action dated July 7, 2026.
In accordance with the MPEP, 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 and the claims drawn to the elected species are allowable, the search of the Markush-type claim will be extended (see MPEP 803.02). 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 reexamined. Id. The prior art search will be extended to the extent necessary to determine patentability of the Markush-type claim. Id. In the event prior art is found during reexamination that renders obvious or anticipates the amended Markush-type claim, the claim will be rejected and the action made final. Id.
As indicated above, the Examiner searched the claimed invention based on the elected species above, wherein: the elected species was found to be allowable over the prior art. The search was expanded to include the additional species described in the rejections herein. Since the scope described herein was not found to be in condition for allowance, it has not been expanded further.
Status of Claims
Currently, claims 1-3, 6-7, 9, 11, 14-17, 20-27, 29, 43 and 45-46 are pending in the instant application. Claims 6-7, 9, 11, 22 and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention and/or species. Claims 1-3, 14-17, 20-21, 23-27, 29, 43 and 46read on an elected species and are therefore under consideration in the instant application to the extent that they read on the elected embodiment and extended scope as indicated above.
Claim Objections
Claims 2-3, 26 and 46 are objected to for depending on a rejected base claim.
Claim Rejections – 35 U.S.C. § 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.
Claim 17 is 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 pre-AIA the applicant regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 17 recites the broad recitations that R2 and R3 are selected from “F, Cl, Br, I, CN, C1-C6 haloalkyl, C1-C6 haloalkoxy and CO2-alkyl.” The claim also recites that the same variables are defined as selected from “Cl, Br and CF3” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the broad recitation in the claim, and therefore not required, or (b) a required feature of the claims.
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 29 and 43 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 specification does not reasonably provide enablement for the claimed methods of preventing and/or treating any and all proliferative disorders or immune disorders or for the prevention of any of the claimed diseases. 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 treatment method for many very broad classifications of diseases, including all cancerous diseases, all diseases having an immunological component, all autoimmune diseases, and all immunodeficiency diseases.
The nature of the invention therefore, is the treatment and prevention of a very broad class of diseases and disorders, many of which would not be reasonably expected to have the same pathologies or be affected by the same receptors and drugs.
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 treat 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 one skilled in the art would not readily recognize, in regards to their preventative effects on depression, whether or not the instantly claimed agents would have any effect.
Further, the treatment of diseases is largely dependent on the source or cause of the disease. The instant claims include diseases for which the causes are largely unknown (e.g. autoimmune diseases) as diseases which are known to be associated with different disease mechanisms (e.g. viral infections are treated differently than bacterial infections which are treated differently than genetic disorders, etc.)
With respect to the autoimmune diseases encompassed by the claimed methods, 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: any and all allergies and allergic reactions, asthma, lupus, nervous system disorders such as multiple sclerosis, Chrons disease, Type I diabetes, Guillain-Barre syndrome, psoriasis, rheumatoid arthritis, and ulcerative colitis. 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. This is a result of the fact that the “underlying mechanisms associated with the pathology of these autoimmune diseases remain unknown” (Wang et al., J. Immunol. 2007, 179, pp.5958-65, See Introduction). For diseases, such as MS, with pathologies that have yet to be discovered there can be no nexus between in vitro tests and in vivo results. That is, although misregulation of T cells is suspected to play a role in MS pathology, because there is no definitive pathology known in the art at this time, it is not possible to say with any confidence that a compound with any particular in vitro assay results will be able to successfully treat a disease which has alluded researches for many years. Although there are known animal models for predicting in vivo efficacy, no animal models were used in the instant specification and assays, such that it would not be possible to correlate the in vitro results presented with a reasonable expectation that the compounds would be effective treatment against multiple sclerosis.
At the time of this application, although there had been substantial progress reported in the scientific literature about the multiple etiologies of multiple sclerosis, including genetic makeup and environmental factors, multiple sclerosis remained a “difficult disease for which solutions seem attainable yet remain elusive.” Compston, A., and Coles, A., “Multiple sclerosis,” The Lancet, vol. 359, pages 1221 – 1231 (April 6, 2002), at page 1224, col. 2, lines 21, et seq. (describing various causes of multiple sclerosis); page 1226, lines 10 et seq. (treatment of multiple sclerosis with β-interferons and synthetic amino acid polypeptides, corticosteroids, etc.), and page 1221, lines 18 – 36 (elusiveness of treatments to treat multiple sclerosis); see also, Hartung, H., et al., “What do we know about the mechanism of action of disease-modifying treatments in MS?” J. Neurol., vol. 251(suppl. 5), pages V/12 – V/29 (2004), at pages V/13, lines 26 - 30 (“even without taking into account the existence of inter-patient heterogeneities, the network of factors that contribute to the pathology and pathogenesis of MS is far from straightforward”); see pages V/15 at lines 12 et seq. (role of cellular mediators such as TNF). At the time of this application, the role of “inflammation” in the development of multiple sclerosis was believed to have both beneficial and detrimental effects. Id. at p. V/16, col. 2, lines 3 – 10 (“Although it is clear that inflammation can have extremely destructive effects [on the course of multiple sclerosis], there is also evidence to suggest that inflammatory reactions may also have beneficial effects that contribute to protective or repair responses”).
Regarding the claimed proliferative disorders, this recitation includes all cancerous diseases. The state of the prior art is that cancer therapy remains highly unpredictable. The various types of cancer have different causative agents, involve different cellular mechanisms, and consequently, different in treatment protocol. It is known that the challenge of cancer treatment has been to target specific therapies to pathogenetically distinct tumor types, that cancer classification has been based primarily on morphological appearance of the tumor, and those tumors with similar histopathological appearance can follow significantly different clinical courses and show different responses to therapy (Golub et al., page 531). Furthermore, it is known that chemotherapy is most effective against tumors with rapidly dividing cells and that cells of solid tumors divide relatively slowly and chemotherapy is often less effective against them. It is also known in the prior art (Lala et al. page 91) that the role of NO in tumor biology remains incompletely understood with both the promotion and inhibition of NO mentioned for the treatment of tumor progression and only certain human cancers may be treated by selected NO-blocking drugs. Because “cancer” refers to a very broad and divergent class of diseases, it is unlikely that there will ever be a single "treatment for cancer." These examples show that there are different cellular mechanisms, there is a lot of unpredictability in the art, and there are very divergent treatment protocols depending on the origin of the cancer and the mechanism of each particular type of cancer.
Specifically regarding the treatment of cancerous tumors, Sausville et al., cited for evidentiary purposes, teaches that traditionally explored tumor model systems are insufficient to predict how actual human beings will respond to treatment in the clinic (page 3351, left column). Even when drugs with evidence of anticancer activity in preclinical in vivo models are given their maximum tolerated dose in humans, they frequently fail to produce useful activity in humans (id.). Also, with regard to unpredictability, Johnson et al., also cited for evidentiary purposes, teach that the in vivo activity of 39 different agents in a particular histology in a tumor model did not correlate to activity in the same human cancer. Further, the mode of action of anticancer agents is often unknown or very unpredictable and administration of such agents is often accompanied by undesirable side effects.
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 a small number of compounds encompassed by the instant claims to inhibit human GPR65. Thus, the issue becomes whether the skilled artisan would conclude that data providing evidence that relatively few compounds of the invention are effective to inhibit one particular receptor is sufficient to extrapolate to the use of millions of different compounds, having substantially different structures, for the treatment of entire classes of diseases which have been notoriously difficult to treat. 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. In addition, there is no guidance regarding how this purported receptor activity would be expected to correlate to not only the treatment, but also the prevention of each of the claimed diseases with the entire scope of the instantly claimed compounds.
The disclosure does not provide how this in vitro data correlates to the treatment 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 breadth of the claims is a method for treatment and prevention of the wide range of diseases and disorders recited in the rejected claims.
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 unpredictability in the pharmaceutical art, as discussed above, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro and in vivo screening to determine which compound exhibits the desired pharmacological activity.
Thus, the specification fails to provide sufficient support of the broad use of the compounds of the instant claims for the treatment of the entire range of all viral infections, 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 and how they could be used to treat any and all liver diseases.
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 claimed disorders.
As a result of the broad and unpredictable nature of the invention and the lack of specific guidance from the specification, it is respectfully submitted that the quantity of experimentation needed to make and or use the invention would be great. Note that there must be sufficient disclosure, either through illustrative examples or terminology, to teach those of ordinary skill how to make and use the invention as broadly as it is claimed. In re Vaeck, 947 F.2d 488, 496 & n.23, 20 USPQ2d 1438, 1445 * n.23 (Fed. Cir. 19991). Also note that the amount of guidance or direction needed to enable the invention is inversely related to the degree of predictability in the art. In re Fisher, 839, 166 USPQ 24. Thus, although a single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements, in cases involving unpredictable factors, such as most chemical reactions and physiological activity, more teaching or guidance is required. In re Fisher, 427 F.2d 839, 166 USPQ 24; Ex Parte Hitzeman, 9 USPQ 2d 1823. Here, 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 diseases can be treated or prevented by the compound encompassed in the instant claims, with no assurance of success.
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."
Claim Rejections - 35 USC §102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
It is noted that with respect to the rejection below, for the purposes of determining if a reference is a “printed publication” for the purposes of 102(a)(1), MPEP 2128 states the following:
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Specifically regarding electronic publications, such as online databases, as prior art the following is noted:
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where “prior art disclosures…on an on-line database are considered to be publicly available as of the date the item was publicly posted.” Since the database entries below list the dates that the compounds were entered into the on-line database, the compounds were made publicly available as of those dates in the citation, and the claims are anticipated.
Claim(s) 1, 14-16, 20-21, 23-25 and 27 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by the STN Registry database entry for CAS RN 2405439-96-3, which has an entry date of 12 January 2020.
Since the entry date represents the date that the compound entered a publicly available database on STN, this represents the date that the compound was made accessible to the public.
The STN Registry database entry listed above discloses the compound
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which reads on the formula (I) where A is a fused pyrimidine ring (ring iii in dependent claim 14); Y is CH2; Ra and Rb are each H; p is 1 and Z is O; q is 0; R15 and R16 are each H and r is 1; R1, R5 and one of R2 and R4 are each H; the other of R2 and R4 is H; and R3 is methoxy. Since the compound disclosed in the prior art has the same structure as the instantly claimed compound, each and every required element of the claim is taught and the claim is anticipated. With respect to the instantly claimed pharmaceutical composition, it is noted that the prior art discloses molar solubility data which describes the anticipatory compound in unbuffered water, which is a pharmaceutically acceptable carrier. Accordingly, the claims are anticipated.
Conclusion
No claims 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.
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/ALICIA L OTTON/Primary Examiner, Art Unit 1699
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