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
Instant application 18/473,282 filed on 09/25/2023 claims benefit as follow:
CONTINUING DATA:
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Status of the Application
Claims 1-11, 13, 14, 23-27 are pending.
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 1-11, 13, 14, 23-27 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 a compound of Formula (I) or pharmacologically acceptable salt thereof, does not reasonably provide enablement for ‘pharmaceutically acceptable ester’ of the compounds of 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/or use the invention commensurate in scope with these claims.
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 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, and 7) the quantity of experimentation needed.
The instant claims recite “A compound of formula (I) ... or a pharmaceutically acceptable acid addition salt, ester, … … thereof” wherein there is insufficient description and/or enablement in the specification regarding the types of ‘pharmaceutically acceptable esters’ intended by the recitation.
The specification provides a definition for the recitation ‘pharmaceutically acceptable ester’ at page 43 and recites that ‘… refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof’. Further, the specification discloses that – “The esters can be formed with an amine, hydroxy, or carboxyl side chain on the compounds described herein”. An ‘ester’ is a chemical compound derived from an acid, for example, a carboxylate ester is represented by the general formula R-C(=O)OR’ wherein R and R’ are any groups selected from hydrocarbons, etc., e.g., alkyl, aryl, etc. However, the compounds of Formula (I) specifically define all the substituents and the specification does not provide which ‘ester’ compound hydrolyzes or breaks down in vivo to leave the parent compound or a salt thereof.
The application neither teaches how to make the claimed ‘pharmaceutically acceptable esters’ that hydrolyze or break down in vivo to a parent compound of Formula (I) nor discloses an example of such ‘pharmaceutically acceptable esters’ within the scope of the claims. Therefore, the application clearly fails to provide a representative number of species of the widely divergent subject matter encompassed by the terms ‘esters’ recited in instant claims.
Beyond the disclosure of a representative number of species, the written descriptionrequirement for a claimed genus may be satisfied through sufficient disclosure of therelevant identifying characteristics of the genus (i.e., structure or other physical and/orchemical properties), by functional characteristics coupled with a known or disclosedcorrelation between function and structure, or by a combination of such identifyingcharacteristics (see MPEP § 2163 (ii)). However, Applicant's specification provides nosuch guidance regarding the terms recited in instant claims, i.e., ‘a pharmaceutically acceptable ester of compound of Formula (I)’. In view of this, the application fails to describe and/or enable the full scope of compounds recited in instant claims.
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a compound of Formula (I) or a pharmaceutically acceptable salt thereof, does not reasonably provide enablement for a crystalline form of a compound of 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/or use the invention commensurate in scope with these claims.
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 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, and 7) the quantity of experimentation needed.
The instant claim recites “The compound of Formula (I) or a pharmaceutically acceptable salt, ... in crystalline form” wherein there is insufficient description or enabling disclosure in the specification regarding the ‘crystalline form’ intended by the recitation. The specification neither describes any crystalline forms of the compounds of Formula (I); nor provides an enabling disclosure of a crystalline form of a compound represented by Formula (I).
‘Crystalline forms’ or the more generically referred term ‘polymorphs’ generally represents natural variations within compounds which themselves may not have any meaningful use. Therefore, determining whether the claimed compounds have or do not have a crystalline form would require determining whether or not there was such physical characteristic within such a sequence and then determining how to use this information in a patentably meaningful way. The instant invention, however, provides no information to this extent.
Searching the pertinent art in the related pyrimidine area did not result in support for such crystalline forms or polymorphs of instant pyrimidine compounds.
Based on the above two facts, a scope of enablement rejection follows using relevant Wands factors. Hence, the burden of establishing the prime facie case is met with.
(i). The nature of the invention and the state of the prior art:
Specification is not adequately enabled as to how to make crystalline form of the claimed compounds and the specification has no example of crystalline forms of any of the compounds represented by Formula (I). Specification neither describes crystalline forms of the compounds nor provides an enabling disclosure of ‘crystalline forms’ of the instant compounds.
The state of the art is that is not predictable whether crystals or polymorphs of a compound will form or what their physical characteristic will be. Thus, in the absence of experimentation one cannot predict if a particular crystalline form of a specific compound will form or not. One cannot predict the stoichiometry of the formed crystal or polymorph.
A state of the art reference, Vippagunta et al., Advanced Drug Delivery Reviews 48: 3-26, 2001, states that formation of crystals or polymorphs is unpredictable. The reference provides that – ‘different crystalline polymorphs differ in crystal packing, and/or molecular conformation as well as in lattice energy and entropy, there are usually significant differences in their physical properties, such as density, hardness, tabletability, refractive index, melting point, enthalpy of fusion, vapor pressure, solubility, dissolution rate, other thermodynamic and kinetic properties, color, etc. Differences in physical properties of various solid forms have an important effect on the processing of drug substances into drug products, while differences in solubility may have implications on the absorption of the active drug from its dosage form, by affecting the dissolution rate and possibly the mass transport of the molecules’, see page 4. Further, the reference provides that: “The main challenge in managing the phenomenon of multiple solid forms of a drug is the inability to predict the number of forms that can be expected in a given case. This prediction would involve quantification of the myriad intermolecular forces within any proposed crystal structure as well as the ability to postulate the likely packing modes for a given molecule in all its configurations. Accurate theoretical prediction of polymorphs from studies of molecular dynamics and crystal structure generation would be of outstanding importance in drug research”, see page 11. In conclusion, the reference provides that "It is important to make every effort to prepare and to identify the most stable polymorph in order to guide the selection of the optimal form for development. The emergence of sensitive methods and the use of combination techniques, facilitate the identification and the more accurate characterization of the various polymorphs of a drug molecule. One of the main challenges faced by the pharmaceutical analyst is the development of better quantitative methods for identifying a single polymorph in the mixture of polymorphs and for determining the percentages of amorphous or crystalline content of the drug", see page 23.
Joachim Ulrich (Kirk-Othmer Encyclopedia of Chemical Technology) provides that “Polymorphism is a condition in which chemically identical substances may crystallize into different forms. Each form is, however, only stable (thermodynamically) in a certain range of temperature and pressure. ... Transitions from one polymorphic form to another may be accompanied by changes in process conditions (temperature, pressure, shear or solution composition), transitions from one polymorphic form to another and lead to formation of a solid product with unacceptable properties (e.g., melting point or dissolution rate)”, see page 3.
(ii). The predictability or lack thereof in the art:
Hence the term ‘crystalline form’ as applied to the compounds claimed by the applicant are not art-recognized forms of the compounds and hence there should be adequate enabling disclosure in the specification with working example(s).
(iii). The amount of direction or guidance present:
The synthetic procedures in the specification and illustrated examples in the experimental section of the specification are limited to making the compounds of Formula (I) and not related to crystalline forms thereof.
(iv). The presence or absence of working examples:
There is no working example of any crystalline form of a compound of Formula (I). The crystalline forms cannot be simply willed into existence. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “[T]he specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However ... there, is no evidence that such compounds exist... the examples of the patent do not produce the postulated compounds... there is ... no evidence that such compounds even exist.” The same circumstance appears to be true here. There is no evidence that crystalline forms of the compounds of Formula (I) actually exist; if they did, they would have formed. Hence, there should be showing supporting that crystalline forms of these compounds exist and therefore can be made.
(v). The breadth of the claims & the quantity of experimentation needed:
Specification provides no support, as noted above, for compounds generically embraced in the claims would lead to desired crystalline form of the compound of Formula (I). The quantity of experimentation needed would be an undue burden on skilled art in the chemical art since there is inadequate guidance given to the skilled artisan for the many reasons stated above. Even with the undue burden of experimentation, there is no guarantee that one would get the product of desired polymorph of compound embraced in the instant claims in view of the pertinent reference teachings.
Claim 14 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating non-Hodgkin’s lymphoma1 or diffuse large B-cell lymphoma2 in a subject comprising administering to the subject an effective amount of a compound of Formula (I), does not reasonably provide enablement for a method of treating all other types of ErbB associated diseases or BTK associated diseases in a subject comprising administering to the subject an effective amount of a compound of 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 use the invention commensurate in scope with these claims.
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 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, and 7) the quantity of experimentation needed. The determination that “undue experimentation” would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations.
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 more 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).
The instant claim 14 is drawn to ‘a method of treating an ErbB associated disease or BTK associated disease in a subject’. First, the instant claim appears to be a 'reach through' claim. Reach through claims, in general have a format drawn to mechanistic, receptor binding or enzymatic functionality and thereby reach through to the corresponding therapeutic method of any or all diseases, disorders or conditions, for which they lack written description and enabling disclosure in the specification thereby requiring undue experimentation for one of skill in the art to practice the invention.
The biological examples 99-104 and the corresponding data in the specification at pages 274-293 provide assays for measuring activity of the compounds for inhibition of EGFR, Her2, BTK and results for exemplified compounds in terms of IC50(nM) and GI50(nM) values are provided in Tables 2-9. There is nothing in the specification to show that the compounds of the present invention are useful in a method of treating all of the ErbB associated diseases and BTK associated diseases.
The instant claims are directed to ‘a method of treating an ErbB associated disease or BTK associated disease in a subject’. The specification at page 57 discloses that ‘examples of ErbB associated diseases include but not limited to, immune-related diseases, proliferative disorders, cancer, and other diseases’ and ‘BTK associated diseases include oncology diseases and autoimmune diseases’. The specification at pages 275-293 provides biological assays and discloses EGFR, Her2, BTK inhibitory activity in specific cell lines (see the Tables at pages 277-293) and results for some of the exemplified compounds are provided therein. Based on the provided biological activity for the compounds, the instant claims recite ‘a method of treating an ErbB associated disease or BTK associated disease in a subject’.
The test data provided in the specification on pages 275-293 is related to in vitro assays of inhibition of EGFR, Her2, BTK and cell proliferation in specific cell lines, and the instant claims are also drawn to ‘a method of treating an ErbB associated disease or BTK associated disease in a subject’. Following the test procedures, the specification provides IC50(nM) and GI50(nM) values for some of the exemplified compounds, however, applicant did not state on record or provide any guidance that the assays provided are correlated to the clinical efficacy of the treatment of various diseases of the claims. It is generally known that the in vitro activity data holds significant role in determining the dosage regimen based on the minimal effective concentration of each of the compound to achieve the desired inhibition of EGFR, Her2, or BTK for each of the type of disease.
The instant claims recite: ‘a method of treating an ErbB associated disease or BTK associated disease in a subject’. First, the instant claims cover 'diseases' that are known to exist and those that may be discovered in the future, for which there is no enablement provided. The use disclosed in the specification is as EGFR, Her2, or BTK kinase inhibitors, useful treating immune-related diseases, autoimmune diseases, proliferative disorders, cancer, oncology diseases, and other diseases. There is nothing in the disclosure regarding how the disclosed in vitro data correlates to the treatment of the various diseases encompassed by the instant claims. The diseases encompassed by the instant claims include various types of autoimmune diseases, cancer, etc. some of which have been proven to be extremely difficult to treat. Further, there is no reasonable basis for assuming that the myriad of compounds embraced by the claims will all share the same physiological properties since they are so structurally dissimilar as to be chemically non-equivalent and there is no basis in the prior art for assuming the same. Note In re Surrey, 151 USPQ 724 regarding sufficiency of disclosure for a Markush group.
See MPEP § 2164.03 for enablement requirements in cases directed to structure-specific arts such as the pharmaceutical art. Receptor activity is generally unpredictable and highly structure specific area. It is inconceivable as to how the claimed compounds can treat all of diseases embraced by the claims. The state of the art is indicative of the unpredictability of the therapeutic approach based on EGFR, Her2, BTK kinase inhibiting activity. A state of the art reference, ten Hacken et al. (Pharmacology & Therapeutics 2014), referring to B-cell receptors indicates ‘BTK as a downstream signaling component’ (see page 342) and concludes that “Randomized trials comparing these kinase inhibitors to established treatments are ongoing, and will provide guidance towards appropriate use of these new drugs. The complexity of the cross talk between malignant B cells and the tissue microenvironment still needs to be better defined to uncover additional therapeutic targets” (see page 344). This is clearly indicative of the fact that the therapeutic role of BTK inhibitors is very speculative.
For example, regarding cancer, no compound has ever been found to treat cancers of all types generally. 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 “silver bullet” is contrary to our present understanding of oncology. The state of the art is not indicative any pharmaceutical agents that are useful in the treatment of cancer generally. Cecil Textbook of Medicine states that “each specific type has unique biologic and clinical features that must be appreciated for proper diagnosis, treatment and study” (see page 1004). Different types of cancers affect different organs and have different methods of growth and harm to the body. Also see In re Buting, 163 USPQ 689 (CCPA 1969), wherein 'evidence involving a single compound and two types of cancer, was held insufficient to establish the utility of the claims directed to disparate types of cancers'. Thus, it is beyond the skill of oncologists today to get an agent to be effective against cancers generally.
Further, there is no established single antiproliferative or anticancer therapeutic agent for all these types of proliferative diseases and/or cancers, which are characterized by the proliferation of tumor cells. The ideal chemotherapeutic drug would target and destroy only cancer cells without adverse effects or toxicities on normal cells. Unfortunately, no such drug exists; there is a narrow therapeutic index between cell kill of cancer cells and that of normal cells. Successful treatment of cancer requires elimination of all cancer cells, whether at the primary site, extended to local-regional areas, or metastatic to other regions of the body. The major modalities of therapy are surgery and radiotherapy (for local and local-regional disease) and chemotherapy (for systemic sites). For example, regarding the treatment of leukemia, The Merck Manual (online edition) states, that “Treatment programs and clinical situations are complex”. Dosage regimen is dependent on several risk factors and the contribution of each active ingredient of a multidrug combination therapy is complex and unclear.
Taken as a whole, the skill level in oncology must be considered as low. "It should benoted that oncology has the lowest success rates of any therapeutic area." Cancer Drug Designand Discovery Neidle, Stephen, ed. (Elsevier/Academic Press, 2008) page 431. There is evensome understanding why this is so. Preclinical testing relies on immortal in vitro cell lines, but"Cell lines derived under artificial conditions and propagated for decades are not likely to berealistic, or to provide meaningful targets" (page 428). The next step is animal models, but"Preclinical efficacy models in cancer drug discovery ... are usually rodent models bearing atransplantable tumor. Yet the vast majority of these investigational drugs fail to meet their pre-specified clinical benefit or efficacy endpoints ... The predictive quality of standard animalmodels has been assessed in a retrospective analysis, with the conclusion that tumor specificitydoes not translate from laboratory to clinic. Human tumor xenografts that present tumors of aparticular histology and tissue of origin do not predict for clinical activity in that tumor" (page427). In other words, successful animal tests with human tumor xenografts with cancer X do notpredict success in humans with cancer X.
The obvious limitations of subcutaneously transplanted xenografts are a) that they do notreside in the same anatomical site as the corresponding tumor in patients; b) that these generallydo not metastasize (which is usually how cancers commonly kill patients); c) that the bloodvessels and stroma are of mouse, not human, origin; and d) that the cells used are from ahomogeneous, not heterogeneous, cell type (real world cancers are normally heterogeneous).Another part of the problem is that it is recognized that anti-cancer drugs are generallyanomalous (as compared to other types of drugs), which greatly limits the ability to use general pharmacological knowledge: "Clearly, the ability to predict acceptable pharmaceutical properties based on chemical structure would be highly desirable. In an attempt to meet this challenge "Lipinski's Rules" were formulated, based on a retrospective analysis of success rates of new orally administered agents entering early clinical trials .... Interestingly, most commonly used cancer drugs fail to satisfy these criteria .... Many marketed anticancer drugs break most of the rules of good pharmacokinetic (PK) behavior" (page 429).
Yet another area of low skill level is the obstacle of poor understanding of resistance mechanisms which so often prevent drug candidates from being successful: "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)" (page 430).
It is not established in the specification how one of ordinary skill in the art would be able to extrapolate the data provided in the specification to the entire scope of the instant claims. See, for example, the state of the art references, Gura et al. (Science 1997) and Johnson et al., (British J. of Cancer 2001) - Gura et al., teaches that researchers face the problem of sifting through potential anticancer agents to find the ones promising enough to make human clinical trials worthwhile and further teach that since formal screening began in 1955, many thousands of drugs have shown activity in either cell or animal models but that only 39 have actually been shown to be useful for chemotherapy (see the first two paragraphs). It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. Also, with regard to unpredictability, Johnson et al., teaches 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. These state of the art references plainly demonstrate that the art of developing and testing anticancer drugs particularly for use in humans is extremely unpredictable, particularly in the case of a single compound or genus of compounds being used to treat any and all cancers.
The diagnosis of each of the disease is generally suggested by medical history and reports of endoscopy, cytology, X-ray, biopsy, etc. depending on the symptoms, signs and complications, which is essential to establish the dosage regimen for appropriate treatment or prevention. The disclosure does not provide any guidance towards the dosage regimen required to facilitate the treatment of the claimed disorders, nor indicate competent technical references in the appropriate methods.
Applicants have not provided any competent evidence or disclosed tests that are highly predictive for the pharmaceutical use of the instant compounds. Pharmacological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The treatment of cancer generally cannot possibly be considered enabled. By way of background, four cases are of particular relevance to the question of enablement of a method of treating cancers broadly or even generally:
In In re Buting, 57 CCPA 777, 418 F.2d 540, 163 USPQ 689, the claim was drawn to “The method of treating a malignant condition selected from the group consisting of leukemias, sarcomas, adenocarcinomas, lymphosarcomas, melanomas, myelomas, and ascitic tumors” using a small genus of compounds. The Court decided that human testing “limited to one compound and two types of cancer” was not “commensurate with the broad scope of utility asserted and claimed”.
In Ex parte Jovanovics, 211 USPQ 907 the claims were drawn to “the treatment of certain specified cancers in humans” by the use of a genus of exactly two compounds, the N-formyl or N-desmethyl derivative of leurosine. Applicants submitted “affidavits, publications and data” for one of the compounds, and a dependent claim drawn to the use of that species was allowed. For the other, no data was presented, applicants said only that the other derivative would be expected to be less effective; claims to the genus were refused.
In Ex parte Busse, et al., 1 USPQ2d 1908, claims were drawn to “A therapeutic method for reducing metastasis and neoplastic growth in a mammal” using a single species. The decision notes that such utility “is no longer considered to be “incredible”, but that “the utility in question is sufficiently unusual to justify the examiner's requirement for substantiating evidence. Note also that there is also a dependent claim 5 which specified “wherein metastasis and neoplastic growth is adenocarcinoma, squamous cell carcinoma, melanoma, cell small lung or glioma.” The decision notes that “even within the specific group recited in claim 5 some of the individual terms used actually encompass a relatively broad class of specific types of cancer, which specific types are known to respond quite differently to various modes of therapy.”
In Ex parte Stevens, 16 USPQ2d 1379 a claim to “A method for therapeutic or prophylactic treatment of cancer in mammalian hosts” was refused because there was “no actual evidence of the effectiveness of the claimed composition and process in achieving that utility.”
MPEP § 2164.01(a) states that “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 and undue experimentation will be required to practice the claimed invention.
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 use of the invention. In view of the breadth of the claim, the chemical nature of the invention, the unpredictability of ligand-receptor interactions in general, 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.
Claims 13 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of inhibiting EGFR, Her2 or BTK by using a compound of Formula (I), does not reasonably provide enablement for a method of inhibiting all other types of ErbB family receptor tyrosine kinases. 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.
In evaluating the enablement question, several factors are to be considered. Note In re Wands, 8 USPQ2d 1400 and Ex parte Forman, 230 USPQ 546. The factors include: 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, and 7) the quantity of experimentation needed. The determination that “undue experimentation” would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations.
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 more 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).
The instant claim is drawn to ‘a method of inhibiting ErbB or BTK by using one or more compounds of Formula (I)’. The specification starting at page 274 provides biological data for exemplary compounds in two types of ErbB: EGFR and Her2. The specification at page 1 provides that ‘ErbB family tyrosine kinases act to transmit signals from the outside of a cell to the inside by activating secondary messaging effectors via phosphorylation event at their tyrosine phosphorylation residues’. The specification discloses that ‘EGFR has been found to be overexpressed and/or mutated in many cancers’; ‘Her2 overexpression can occur in breast, ovarian, bladder, non-small cell lung carcinoma, as well as several other tumor types’, see page 2. The instant claim appears to be a 'reach through' claim. Reach through claims, in general have a format drawn to mechanistic, receptor binding or enzymatic functionality and thereby reach through any or all diseases, disorders or conditions, for which they lack written description and enabling disclosure in the specification thereby requiring undue experimentation for one of skill in the art to practice the invention.
The specification does not provide sufficient guidance to one of ordinary skill in the art to test the scope of instantly claimed ‘ErbB inhibition’ activity. The specification at pages 44-45 provides that “ErbB or wild-type ErbB refers to normal ErbB family members” and ‘the term “mutations” refers to any mutations to the ErbB protein’. The specification does not provide description of the scope covered by the term ‘ErbB protein’ and/or the sources for the various ErbB proteins encompassed within the ErbB family. A state of the art reference, Zhou et al. (Bioinformatics 2007) provides that “Proteins function through interactions with other proteins and biomolecules. Protein-protein interfaces hold key information toward molecular understanding of protein function” (see Abstract). Another state of the art reference, Hanks et al., regarding protein kinases provides that – ‘protein kinases make up a large superfamily of homologous proteins’ (see abstract). Further, the referenced teaches that: “One of largest known protein superfamilies is made up of protein kinases identified largely from eukaryotic sources. … … The protein kinases are related by virtue of their homologous kinase domains (also known as catalytic domains), which consist of 250-300 amino acid residues. … … Consequently, about 200 different superfamily members (products of distinct paralogous genes) had been recognized from mammalian sources alone! The prediction made several years ago that the mammalian genome contains about 1000 protein kinase gens (roughly 1% of all genes) would still appear to be within reason, and may even be an underestimate” (see page 576).
The instant specification provides biological data for testing the inhibiting activity related to specific types of kinases: EGFR, Her2, and BTK. There is no other experimental data related to any other ErbB proteins or ErbB receptor tyrosine kinase family. Applicant did not state on record or provide any guidance that which state of the art assays may provide basis for the full scope of the instantly claimed ErbB inhibition activity. Further, there is no disclosure regarding how this potential ErbB protein inhibitory activity in a subject is correlated to the clinical efficacy of the treatment of various diseases or disorders disclosed in the specification. See MPEP § 2164.03 for enablement requirements in cases directed to structure-specific arts such as the pharmaceutical art.
Applicants have not provided any competent evidence or disclosed tests that are highly predictive for the instantly claimed ‘method of inhibiting ErbB’. Pharmacological/physiological activity in general is a very unpredictable area. Note that in cases involving physiological activity such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved”. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
MPEP § 2164.01(a) states that “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 and undue experimentation will be required to practice the claimed invention.
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 use of the invention. In view of the breadth of the claim, the chemical nature of the invention, the unpredictability of ligand-receptor interactions in general, and the lack of working examples regarding the activity of the claimed compounds of formula (I), 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 claim.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-11, 13, 14, 23-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11,007,198. Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims substantially overlap the compounds of the reference claims; and or the compounds according to instant claims are structurally analogous to reference claimed compounds.
The reference claims are drawn to compounds of Formula (I), see the structural formula in claim 1 (relevant portion from reference claims are provided below for convenience); and the specific compounds recited in claim 2.
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The compounds are taught to be useful as pharmaceutical agents, see claims 3-5. The reference disclosure provides that ‘the compounds inhibit ErbB (e.g., EGFR or Her2) and/or BTK and useful in treatment of diseases associated with mutant forms of ErbB and/or BTK’, see col. 1.
Further, regarding instant claims 23 -24, the reference claims recite:
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The instant claims differ from the reference claims by reciting a genus that encompasses the genus of the structural formula of reference claim 1 and/or the species recited in claim 2. In other words, the instant claims differ by reciting a genus covering the subgenus and/or species recited in claims of U.S. Patent No. 11,007,198 (reference claims), and the use consistent with reference disclosure.
It would have been obvious to one having ordinary skill in the art at the time of the invention to select any of the compounds from the reference claims, including those instantly claimed, because the skilled artisan would have had the reasonable expectation that any of the species of the genus would have similar properties and, thus, the same use as taught for the genus as a whole i.e., as pharmaceutical agents. One of ordinary skill in the art would have been motivated to select the claimed compounds from the genus in the reference since such compounds would have been suggested by the reference as a whole.
Claims 25-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 11,007,198 in view of Syed (Yahiya Y. Syed, Drugs (2017) 77:1369–1376).
The recitations of claims of U.S. Patent No. 11,007,198 have been discussed above and those recitations are incorporated herein by reference.
The claims of U.S. Patent No. 11,007,198 recite:
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The claims of U.S. Patent No. 11,007,198 do not recite the therapeutic agents recited in instant claims 25-27.
However, the anti-tumor agents recited in instant claims 25-27 have been disclosed in prior art.
For example, Syed teaches durvalumab, PD-L1 inhibitor, for treatments of cancers (see page 1361 – Introduction):
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Further, Syed teaches durvalumab in combinations with different anti-tumor agents (see page 1374, last paragraph):
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Since durvalumab is a known PD-L1 inhibitor used alone or with different anti-tumor agents for treatments of cancers - Applying KSR prong (A) – Combining prior art elements according to known methods to yield predictable results - it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the compounds recited in U.S. Patent No. 11,007,198 with durvalumab with a reasonable expectation of success.
MPEP 2144.06 states that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”.
In the instant case, one of ordinary skill in the art would have been motivated to combine the compounds recited in U.S. Patent No. 11,007,198 with durvalumab to achieve cumulative therapeutic effect in treatments of cancers.
Claims 1-11, 13, 14, 23-24 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11504375. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of U.S. Patent No. 11504375 recite the same compounds as instant claims.
Further, U.S. Patent No. 11504375 recite a method of inhibiting EGFR, Her2 or BTK and a method of treating an ErbB associated disease or BTK associated diseases in a subject:
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The methods recited in claims of U.S. Patent No. 11504375 fall under the methods recited in instant claims 13 and 14.
Regarding instant claims 23-24, the claims of U.S. Patent No. 11504375 recite:
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Since the claims of U.S. Patent No. 11504375 meet all the limitations of instant claims, the instant claims are anticipated.
Claims 25-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11504375 in view of Syed (Yahiya Y. Syed, Drugs (2017) 77:1369–1376).
The recitations of claims of U.S. Patent No. 11504375 have been discussed above and those recitations are incorporated herein by reference.
The claims of U.S. Patent No. 11504375recite:
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The claims of U.S. Patent No. 11504375 do not recite the therapeutic agents recited in instant claims 25-27.
However, the anti-tumor agents recited in instant claims 25-27 have been disclosed in prior art.
For example, Syed teaches durvalumab, PD-L1 inhibitor, for treatments of cancers (see page 1361 – Introduction):
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Further, Syed teaches durvalumab in communications with different anti-tumor agents (see page 1374, last paragraph):
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Since durvalumab is a known PD-L1 inhibitor used alone or with different anti-tumor agents for treatments of cancers - Applying KSR prong (A) – Combining prior art elements according to known methods to yield predictable results - it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the compounds recited in U.S. Patent No. 11504375 with durvalumab with a reasonable expectation of success.
MPEP 2144.06 states that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”.
In the instant case, one of ordinary skill in the art would have been motivated to combine the compounds recited in U. S. Patent No. 11504375 with durvalumab to achieve cumulative therapeutic effect in treatments of cancers.
Claims 1-11, 13 and 14 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11896597. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of U.S. Patent No. 11896597 are directed to a specific species (specific composition and specific diseases) falling within the instant genus.
The claims of U.S. Patent No. 11896597 recite:
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Further, the claims of U.S. Patent No. 11896597 recite:
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MPEP 2131.02 states “A generic claim cannot be allowed to an applicant if the prior art discloses a species falling within the claimed genus." The species in that case will anticipate the genus. In re Slayter, 276 F.2d 408, 411, 125 USPQ 345, 347 (CCPA 1960); In re Gosteli, 872 F.2d 1008, 10 USPQ2d 1614 (Fed. Cir. 1989) (Gosteli claimed a genus of 21 specific chemical species of bicyclic thia-aza compounds in Markush claims. The prior art reference applied against the claims disclosed two of the chemical species. The parties agreed that the prior art species would anticipate the claims unless applicant was entitled to his foreign priority date.)”
Since the species (specific composition and specific diseases) recited in claims of U.S. Patent No. 11896597 fall within the instant genus, therefore, the instant claims are anticipated.
Claims 23-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of U.S. Patent No. 11896597 in view of Syed (Yahiya Y. Syed, Drugs (2017) 77:1369–1376).
The recitations of claims of U.S. Patent No. 11896597 have been discussed above and those recitations are incorporated herein by reference.
The claims of U.S. Patent No. 11896597 do not recite a combination with a second therapeutic agent.
However, combination therapies for cancers have been disclosed in prior art.
For example, Syed teaches durvalumab in combinations with different anti-tumor agents (see page 1374, last paragraph):
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It should be noted that durvalumab is PD-L1 inhibitor for treatments of cancers (see page 1361 – Introduction):
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Since durvalumab is a known PD-L1 inhibitor used alone or with different anti-tumor agents for treatments of cancers - Applying KSR prong (A) – Combining prior art elements according to known methods to yield predictable results - it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the compounds recited in U.S. Patent No. 11896597 with durvalumab with a reasonable expectation of success.
MPEP 2144.06 states that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980)”.
In the instant case, one of ordinary skill in the art would have been motivated to combine the compounds recited in U.S. Patent No. 11896597 with durvalumab to achieve cumulative therapeutic effect in treatments of cancers.
Conclusion
No claim is allowed.
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/I.S./Examiner, Art Unit 1621
/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621
1 OCI-LY-10 – non-Hodgkin’s lymphoma cell line (see https://www.ebi.ac.uk/ols/ontologies/efo/terms?short_form=EFO_0006708)
2 TMD8 - diffuse large B cell lymphoma cell line (see https://www.ebi.ac.uk/ols/ontologies/efo/terms?short_form=EFO_0006496)