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 1,3,9, 11, 14, 16-17, 19, 21, 26, 29, 33-37, 39-40, 43-48 are pending
And **are under consideration in the instant office action.
Election/Restrictions
Applicant’s election without traverse of the following species in their response dated 06/05/2026 is acknowledged.
Specie 1: Compound: Applicants elect the following compound 6 with the following formula.
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Specie election 2: It is noted that the applicants were required to elect a single disclosed specie of the disease mediated by KRAS and/or PI3K in their response. The election of species was not to pick between specie election 1 and Specie election 2. Examiner at this point will examine the instant claims 45-48 for all the disease it encompases.
Examination of the claims are conducted to the extent they read on the elected species..
Claims 1,3,9, 11, 14, 16-17, 19, 21, 26, 29, 33-37, 39-40, 43-48 are under examination and the requirement for restriction is made final.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 03/22/2024 and 06/08/2026 complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits. See attached copy of the PTO-1449.
Priority
This application claims benefit of international Application No. PCT/CN2022/l 20154. filed on September 21, 2022. which is based upon and claims priority to Chinese Patent Applications No. 2021111l081 76.5, filed on September 22. 2021. No 202210089257.3. filed on January 25, 2022, and No. 202210227315.4. tiled on March 08. 2022.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 1,3,9, 11, 14, 16-17, 19, 21, 26, 29, 33-35, 37, 39-40, 43-48 are rejected under 35 U.S.C. 112, first paragraph, , because the specification, while being enabling for the specific compounds, compound ‘s recited in instant claim 36, does not reasonably provide enablement for all the compounds encompassed by the formula recited in instant claims encompassed by formula I
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention and Breadth of claims:
As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.” In the instant case, the claimed invention pertains to compounds of Formula I, which allegedly effective as a KRASG12C inhibitor and/or P13K protein inhibitor
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First with regards to the formula recited in instant claim 1, it encompasses a large number of possible structural components for each variable of the compound of formula recited in instant claim 1.. The formula contains many variables and each variable is defined by substituents which include heterocyclic moieties and are further substituted. For example B1 and B2 which includes 5-10 membered nitrogen-containing heterocycloalkenyl, spirocyclicor bridged cyclic rings and R5 and R6 groups which include hydrogen, halogen, cyano, alkyl, aliphatic heterocyclyl, aryl, heteroaryl, -ORa, -NRbRC, -C(O)R16, -S(O)R16, -S(O)2R16, -P(O)R16R17, -C(O)NRbRc or - C(O)ORa, wherein the alkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally substituted and variables R12, R12', R13, R13', R13", R7, R7' is independently selected from hydrogen, halogen, cyano, alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl, -OR", -NRRP, - 3 C(O)R20, -C(O)NRRP or -C(O)OR", wherein alkyl, cycloalkyl, aliphatic heterocyclyl, aryl, heteroaryl are optionally substituted. These compounds encompass molecules that widely vary in the physical and chemical properties such as size, molecular weight, acidity, basicity, and properties that are known in the art to greatly influence pharmacokinetic and pharmacodynamics parameters, not to mention the ability to productively bind to claimed biological target molecules. The claims cover compounds easily in the millions given the number of possible rings, ring systems covered by the claims' scope along with varying choices for remaining variables.
The claims encompass a plethora of structurally divergent compounds and there is no evidence of record that the broad scope of the claimed compounds have the biological activity asserted by the applicants which is also very broad that is to treat any disease or injury in the subject.
The State and Predictaility in the art, and relative skill of those in the art:
“[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” As discussed above, the instantly claimed invention pertains to method of treating bacterial infection with compounds of formula I which are alleged by the Specification to be useful for that purpose. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response. The relative skill of those in the art is high, generally that of an M.D. or Ph.D That factor is outweighed, however, by the unpredictable nature of the art. 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, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.), Nationwide Chemical Corporation, et al. v. Wright, et al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances), Ex parte Sudilovsky 21 USPQ 2d 1702 (Appellant's invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable).
Once a compound has been identified by ligand based and/or structure based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised.
The skilled artisan would view the synthesis of every possible variation of the compounds encompassed by formula I as requiring much experimentation. In addition, the basis of the activity of the instantly claimed compounds as claimed is by its ability to act as KRASG12C inhibitor and/or P13K protein inhibitor. As such the ability of any of the encompassed compounds to effectively act as the inhibitors as as claimed resulting in therapeutic utility is highly unpredictable and requires undue amount of experimentation.
Amount of guidance/Existence of working examples:
As stated above, the compounds made are not representative of the instant scope but are closer to each other than to remaining scope. The instant specification discloses the preparation of several compounds of the instant specification, but the formula I encompasses thousands of compounds that the instant specification is not enabled for.
Absence of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164.
The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, one of skill in the art would not accept the assertion that a majority of the compounds encompassed by the claims can be prepared and also be effective as KRASG12C inhibitor and/or P13K protein inhibitors. As such, the only way to ascertain which of the hundreds of claimed compounds encompassed by Formula I are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent 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" (42 USPQ 2d 1001, Fed. Circuit 1997).
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no reasonable assurance of success.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 39, 40 and 45-48 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for inhibition of KRASG12C inhibitor and/or P13K protein inhibitor and treatment of lung and pancreatic cancer with the compounds recited in instant claim 36, does not reasonably provide enablement for the treatment of any and every disease mediated by KRAS and or P13L by administering th each and every compounds encompassed by the formula I recited in instant claims. 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 claims are directed to a method of treatment a subject having a disease or injury comprising administering to said subject a compound of formula (I) recited below. Accordingly the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
The invention is drawn to a method of treating a disease mediated by KRAS and/or PI3K and method of treating a disease that is resistant to anticancer agents, comprising administering to a subject in need thereof a therapeutically effective amount of the compound of formula I shown below
Breadth of the claims
The breadth of the claims is extensive. The claims relate to an extremely large number of possible compounds as recited in the 112 rejection of claim 1 above , which are all supposed to be effective in the treatment of any of the diseases mediated by KRAS and/or P13K. The diseases mediated by these two genes include many different types of Cancers and autoimmune diseases. Cancers are highly varied, while the claims narrows down the types of cancers to be treated, it is noted that these cancers are not a single disease, or cluster of closely related disorders. There are hundreds of cancers, which have in common only some loss of controlled cell growth. Cancers are highly heterogeneous at both the molecular and clinical level, treatment methods and prognosis is very specific to the type of cancers.
the scope of autoimmune disorders is unclear.
The “autoimmune diseases” are processes that can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. There are dozens of such diseases, which have fundamentally different mechanisms and different underlying causes, often unknown. Autoimmune diseases constitute a diverse collection of disorders in which dysregulated innate and adaptive immunity results in production of autoantibodies, autoreactive T-cell clones, and tissue damage including necrosis, scarring and organ dysfunction. There is no single mechanism to explain the initiation, course and natural history of autoimmune diseases generally.
In addition the number of compounds encompassed by the formula I is also extremely vast since they encompass a large number of possible structural components for each variable of the compound of formula (as noted in the 112 rejection above)
State of the prior art/Predictability or unpredictability of the art:
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). While some cancers can be treated in some hosts using specific compound or combination of agents, the effective treatment of various forms of cancer and the use of structurally related compounds remains a highly unpredictable art. State of the art cancer research comprises laborious time-consuming and costly experimental methods comprising functional and non-functional assays representing both in vitro and in vivo experiments. The Applicant' s attention is directed towards an excerpt from Neidle' s Cancer Drug Design and Discovery (Elsevier/Academic Press, 2008, pages 427-431; cited in PTO-892). Neidle notes that oncology has the lowest success rates of any therapeutic area (page 431). Neidle states, “…tumor specificity does not translate from laboratory to clinic. Human tumor xenografts that present tumors of a particular histology and tissue of origin do not predict for clinical activity in that tumor” (page 427, column 2) and “cell lines derived under artificial conditions and propagated for decades are not likely to be realistic, or to provide meaningful targets” (page 428, column 1). Thus, even a highly skilled practitioner in the art would not be able to predict whether or not a claimed treatment for cancer would be efficacious based on in vitro and in vivo models. Of particular concern is the development of resistance to therapeutics. “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)" (page 430).
Further, the prevention of any disorder presents a formidable challenge. The prophylaxis of any disorder requires a certainty of success that the disorder will not develop. Even in the hands of a skilled artisan, the pharmaceutical arts are unpredictable, particularly due to the complexity of molecular signaling pathways. Many disorders have complex pathologies involving multiple proteins. Inhibition of one pathway does not guarantee that the disorder would not arise via a different signaling pathway. Thus, one having ordinary skill in the art would not have a reasonable expectation of success in a method for the complete prevention of a disease.
Thus the art of cancer research remains highly unpredictable. Currently there is no treatment that would have an expectation of success in treating any and all cancers.
The present claims relate to the mechanism underlying the treatment of the claimed diseased with the compounds of the instant invention. Although the discovery of such a mechanism may be an important piece of scientific knowledge, it still needs to be turned into a practical application in the form of a specified actual treatment of the pathological conditions.
The state of the prior art is such that it involves screening both in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. which compounds treat which specific amyloid associated disease). 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 regimen on its face.
The amount of direction or guidance presented and the presence or absence of working examples:
In terms of specific cancer, Applicants provide two examples which details the ability of a list of compounds in inhibiting the cancer cells in in-vitro assays in NBCI-H538 cell line (non-small cell lung cancer) and in human MIA PaCa2 (pancreatic ductal adenocarcinoma cell line). This is not a fair representation of the hundreds of compounds encompassed by the compound of formula I and hundreds of different types autoimmune conditions or cancers encompassed by the broad term KRAS/PI3K mediated diseases. Further it is noted that The dosage range information provided is completely generic. That is, it is the same dosage for the agents for all different disease covered in the specification, which is a very substantial range of disorders. As such, the direction and guidance presented by the applicant in the disclosure is minimal and does not enable one of ordinary skill in the art to use the claimed invention in the method of treatment of various diseases covered by the claims. Applicant's specification does not set forth a representative number of examples of cancers, which would be treated by the claimed compounds. The specification fails to provide scientific data and working embodiments with respect to a method of treating different types of cancer using all of the possible compounds of formula I which function as KRAS or PI3K inhibitors..
The quantity of experimentation necessary
Given the fact that, historically, the development of new cancers drugs has been difficult and time consuming, and especially in view of factors above, the quantity of experimentation needed is expected to be great.
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, one of skill in the art would not accept the assertion that a majority of the compounds encompassed by the claims would be effective in treating any of the bacterial strains tested, let alone against all bacterial strains, or that the explicitly disclosed compounds would be effective against a majority of bacterial species.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent 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" (42 USPQ 2d 1001, Fed. Circuit 1997).
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here. Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no reasonable assurance of success.
Conclusion
Claims 1,3,9, 11, 14, 16-17, 19, 21, 26, 29, 33-37, 39-40, 43-48 are rejected. No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAVITHA M RAO/ Primary Examiner, Art Unit 1691
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