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 .
Election/Restrictions
Applicants’ election with traverse of Group II, corresponding to claims 1-16 and 19, in the reply filed on August 3, 2026, is acknowledged. The traversal is on the ground(s) that the claims were amended. The examiner notes that the restriction requirement was based on the claims as presented at the time the requirement mailed. The examiner will consider rejoinder at the appropriate time. Further, even if the prior art did not recognize the functionality of claimed compounds as argued, the properties are secondary to the compounds themselves. Thus, whether recognized or not, compounds have the functionality that their structure imparts.
The requirement is still deemed proper and is therefore made FINAL.
Applicant elected the following species: compound Z568 with the following structure-
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. The claims that read on the elected species are 7-9, 14-16, and 19.
The elected species is free of prior art. The examiner has applied Scope of Enablement and Written Description Rejections below.
Status of the Claims
Claims 1-19 are pending. Claims 1-6, 10-13, 17, and 18 are preliminarily withdrawn. Claims 7-9, 14-16, and 19 are examined.
Claim of Foreign Priority
Applicants’ claim of foreign priority and Certified Copy of Foreign Priority documents have been received by the Office.
Suggestions for Allowance:
Claims 14 and 19 are directed to allowable subject matter should the term “prodrug” be removed from the claims to overcome the § 112 Rejections.
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 7-9, 14-16, and 19 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the compounds set forth in claim 14, are not considered enabled for the other compounds encompassed by Formula (IC ) nor their prodrugs. 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.
The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below
Nature of the Invention: 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 (IC), which are alleged by the Specification to act as inhibitors of SLP76 phosphorylation (Table 2), and inhibitors of HPK1 (Table 3). See Specification, pages 377-381.
The State of the Prior Art and the Relative Skill of those in the Art: As stated in MPEP 2164.05(a), “[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 compounds of Formula (I), which are alleged by the Specification to act as inhibitors of SLP76 phosphorylation (Table 2), and inhibitors of HPK1 (Table 3). 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 Level of Predictability in the Art: 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. 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. A 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 Amount of Direction Provided by the Inventor / Existence of Working Examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the Specification discloses approximately 356 compounds species encompassed by Formula (IC), which are inhibitors of SLP76 phosphorylation (Table 2), and inhibitors of HPK1 (Table 3). Table 2 provides examples of IC50 values for SLP76 inhibition with considerable distinctions in potency despite similar structures.
There is no pharmacokinetic data provided as only cellular assays were conducted.
Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “when a compound or composition claim is not limited by a recited use, any enabled use that would reasonably correlate with the entire scope of that claim is sufficient to preclude a rejection for nonenablement based on how to use” (emphasis added). Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, 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 (Fed. Cir. 1993) (emphasis added).
At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims". Amgen, Inc., v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
As to the first inquiry, as discussed above, the claims are drawn to compounds of Formula (IC), which are alleged by the Specification to as inhibitors of SLP76 phosphorylation (Table 2), and inhibitors of HPK1 (Table 3). Considering that Formula (IC) encompasses tens of thousands of compound species or more, it is evident that the claims are broad. Yet, as discussed above, the instant Specification discloses approximately 356 similarly structured compound species encompassed by Formula (IC) as recited by the claims. As such, the claim is extremely broad with respect to the disclosure. The second inquiry is discussed in detail below.
Amount of Experimentation Necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to compounds of Formula (I), which are alleged by the Specification to act inhibitors of SLP76 phosphorylation (Table 2), and inhibitors of HPK1 (Table 3). Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of Formula (IC) with respect to the disclosure since Formula (IC) encompasses at least tens of thousands of compound species, whereas the instant Specification discloses only 356 such compound species exerting the disclosed activity. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan (armed with screening techniques including computer assisted virtual screening techniques such as ligand-based and structure-based design methods) could not reasonably predict which of the thousands of compounds encompassed by Formula (I) would exert the alleged activity based on the limited disclosure of 356 similarly structured active compounds with a high degree of variability. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similar activity, the skilled artisan would have also known 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.
For example, the 356 compounds taught by the Specification are split with activity level. Compounds Z309-2, Z313, Z449, Z385 provide no data for SLP76 inhibition. Further, the IC50 values for Z3-1, Z3-2, Z113, Z231, is >10,000 while the IC50 value for compounds Z447, Z528, Z572, Z385 (3.3), Z388, and others is less than 50. Table 3 provides a similar breadth in IC50 values. For example compound Z234-2 has a value of >1000 while Z93-2 has a value of 0.71. Additionally, Z239, Z281, Z313 provide no data for HPK1 inhibition.
Despite these significant differences in inhibitory potency and a lack of data for numerous compounds, the structural similarities for those compounds tested is substantially narrower than that claimed.
For example, the following moieties are present in almost all of the claimed examples:
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; and
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; and
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or
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. The variability is substantially less in the embodiments of the instant Specification for each of R1, Z, Cy1, Cy2, R4, and others. R4 appears to be methyl in most examples in a single position. Despite this and with the examiner acknowledging that some examples show an alkyl, halogen or CN, the claim includes the following definition, in part, for R4:
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The examiner notes that the IC50 data differs significantly for similar structures. This definition for R4 includes hundreds of thousands or more permutations wherein R4 is shown to be tested with limited variability.
Similarly, Cy2 is defined as follows, in part:
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Despite the lack of variability of those compounds set forth in the Specification and the substantially differences in IC50 values, the instant claims include thousands of permutations and do not require structural limitations that are present in all or substantially any of the structures of the embodiments shown in the Specification.
Thus, in order to identify usable compounds of Formula (I), the skilled artisan (at minimum) would have to carry out ligand based drug design methods using the 356 disclosed compounds as a starting point and, assuming the structure of the target receptor was known, combine the findings with data derived from structure based drug design methods to arrive at a small library of “lead” compounds believed to possess the activity of interest. The skilled artisan would then synthesize lead compounds that are within Formula (IC) for in vitro testing. Given the unpredictability of the chemical arts, it is highly unpredictable whether any compound within the subgenus of compounds of Formula (IC) identified by rational drug design based on the instant disclosure would, in fact, be usable. Whether the other compounds of Formula (IC) (i.e., those not identified by rational drug design based on the instant disclosure) would be usable is even less predictable. As such, the only way to ascertain which of the hundreds of millions, and potentially billions, of claimed compounds encompassed by Formula (IC) 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.
Claim Rejections - 35 USC § 112 (Written Description)
Claims 7-9, 14-16, and 19 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. Following reasons apply:
Claims 7-9, 14-16, and 19 include a compound or prodrug of a compound of Formula (IC). The claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. Specifically, claim 7 recites a prodrug of the claimed compound.
The MPEP §2163 states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. In the case of chemical entities, Applicant's attention is further directed to Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089, 118 S. Ct. 1548 (1998), which holds that an adequate written description requires a precise definition, such as by structure, formula, chemical name, or physical properties, "not a mere wish or plan for obtaining the claimed chemical invention." Eli Lilly, 119 F.3d at 1566. Furthermore, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. Although the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus, if the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. While the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad generic. For example, in In re Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872, F.2d at 1012, 10 USPQ2d at 1618.
The Federal Circuit has adopted the standard set forth in the Patent and Trademark Office (PTO) Guidelines for Examination of Patent Applications under the 35 U.S.C. 112.I "Written Description" Requirement ("Guidelines"), 66 Fed. Reg. 1099 (Jan. 5, 2001), which state that the written description requirement can be met by "showing that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics," including, inter alia, "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention" Enzo Biochem, Inc. v. Gen-Probe Inc., 296 F.3d 316, 1324-25 (Fed. Cir. 2002) (quoting Guidelines, 66 Fed. Reg. at 1106). Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient. MPEP §2163. However, if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is “not sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence.” MPEP §2163.
The instant claims are drawn to a claimed structure and prodrugs thereof.
Level of skill and knowledge in the art: The level of skill in the art is high.
Partial structure: The claimed structure has been disclosed and example compound species that would be within the claimed structure have been disclosed. However, as to the claimed prodrugs, no specific examples are given that would demonstrate possession of or put the public in possession of the claimed prodrugs of the claimed structure.
Physical and/or chemical properties/Functional characteristics: The compound claimed, including the prodrugs, are compounds which are allegedly useful to antagonize/inhibit CB1. Although the art recognizes the above definitions the terms are not explicitly defined by the specification in such a way as to demonstrate that the inventor had possession of the claimed prodrugs.
Predictability of the Art: It is generally accepted in the art that formation of a particular prodrug for a given compound or series of compounds is unpredictable.
As stated by Stella et al. (Prodrugs: Challenges and Rewards, Part 1, 2007) (attached), the personnel and skills needed for a successful prodrug program “are no different from those for analog development – it takes a team. The ideal drug is one that is active, easy to formulate, well absorbed after oral dosing, has an acceptable PK profile, and is both renally cleared and metabolized to 1-2 non-toxic metabolites that are rapidly excreted after being formed. If a prodrug intervention is necessary, obviously this ideal scenario is not met. The ideal prodrug, therefore, is one that readily achieves its desired goal, is non-toxic, and breaks down efficiently and quantitatively to the drug and known and safe by-products. Like the drug discovery process, this goal is not often met” (Page 24, Paragraph 3, emphasis added).
Method of making the claimed invention: Although the Specification provides a method for making the elected compounds, no method for making a prodrug has been disclosed.
Summary: In the instant case, Applicant has not disclosed the structure, formula, chemical name, or physical properties of the numerous prodrugs of compounds of formula (A). Although some functional characteristics are disclosed or would be known to a person of ordinary skill in the art, in the absence of a disclosed structure, there can be no correlation between the function and structure of the claimed prodrug compounds.
However, the MPEP states that written description for a genus (for example, the claimed prodrugs or active metabolites of the elected compound species) can be achieved by a representative number of species within a broad generic. It is unquestionable that the claim(s) are broad and generic with respect to all possible compounds encompassed by the claims: the possible structural variations are limitless to any prodrugs of formula (IC). In the instant case, however, the Specification does not disclose a sufficient variety of species to reflect this variance in the genus. While having written description of the elected compound and compounds identified in the Specification tables and/or examples, the Specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims such as, for example, prodrugs.
The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736, F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does “little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate.”) Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
As such, no claim is allowed.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628
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