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 .
Claim of Foreign Priority
There is no claim of foreign priority.
Status of the Claims
Claims 1, 28-31, 37, and 49 are pending and examined.
Allowable Subject Matter
Claims 28 and 29 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The closest prior art are those references cited in the ISR. However, Luan et al.,US2023/0286947 has at least two structural differences from the instant claims. The first is the position of the pyridine nitrogen atom. The second is the length and form of linker connecting substituents on the nitrogen containing heterocycle. There is no motivation to arrive at the claimed compounds in view of the those described by the cited prior art.
Claim Rejections - 35 USC § 112
Claim 37 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 37, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Further, the terms “inappropriate” or “undesirable” are relative terms that are not clearly defined such that the metes and bounds are well-defined.
Claim Rejections - 35 USC § 112
Claims 31 and 49 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:
Claim 31 is directed to treating any condition and claim 49 is directed to a compound of Formula (I) in combination with any agent or combination of agents.
As explained by Bulusu et al., “Modelling of compound combination effects and applications to efficacy and toxicity: state-of-the-art, challenges and perspectives,” Drug Discovery Today, Volume 21, Issue 2, February 2016 pages 225-238:
The development of treatments involving combinations of drugs is a promising approach towards combating complex or multifactorial disorders. However, the large number of compound combinations that can be generated, even from small compound collections, means that exhaustive experimental testing is infeasible.
As such, with testing being infeasible and complex, it is imperative that Applicant provide some showing or rationale to be able to arrive at a claimed combination for treating the vast breadth of conditions claimed but also for having an understanding of the potential drug-drug interactions (DDI) that may alter efficacy and/or toxicity.
The Specification describes several compounds that are alleged to treat a number of conditions. However, the Specification refers to using additional therapeutic agents 6 times without referring to a single specific example of any secondary agent.
The written description requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor's obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of claimed invention.
Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and demonstrate that by disclosure in the specification of the patent.
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003).
Written description requirement, serves both to satisfy the inventor's obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed. A patentee can lawfully claim only what he has invented and described, and if he claims more his patent is void.
See MPEP 2163.01-02 for General principles governing compliance with the written description requirement applications. 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention The written description requirement has several policy objectives. “[T]he ‘essential goal’ of the description of the invention requirement is to clearly convey the information that an applicant has invented the subject matter which is claimed.” In re Barker, 559 F.2d 588, 592 n.4, 194 USPQ 470, 473 n.4 (CCPA 1977). Another objective is to convey to the public what the applicant claims as the invention. See Regents of the Univ. of Cal. v. Eli Lilly, 119 F.3d 1559, 1566, 43 USPQ2d 1398, 1404 (Fed. Cir. 1997), cert. denied, 523 U.S. 1089 (1998). "The ‘written description’ requirement implements the principle that a patent must describe the technology that is sought to be patented; the requirement serves both to satisfy the inventor’s obligation to disclose the technologic knowledge upon which the patent is based, and to demonstrate that the patentee was in possession of the invention that is claimed." Capon v. Eshhar, 418 F.3d 1349, 1357, 76 USPQ2d 1078, 1084 (Fed. Cir. 2005). Further, the written description requirement promotes the progress of the useful arts by ensuring that patentees adequately describe their inventions in their patent specifications in exchange for the right to exclude others from practicing the invention for the duration of the patent’s term.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that “a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "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".
Whenever the issue of written description arises, the fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991). An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Am. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). MPEP 2163.02).
Whether the written description requirement is satisfied is a fact-based inquiry that will depend on the nature of the claimed invention and the knowledge of one skilled in the art at the time an invention is made and a patent application is filed. The written description requirement is not satisfied by the appearance of mere indistinct words in a specification or a claim, even an original claim. . A description of what a material does, rather than of what it is, usually does not suffice." Enzo, 323 F.3d at 968 (citing Eli Lilly, 119 F.3d at 1568); see Rochester, 358 F.3d at 926 ("[G]eneralized language may not suffice if it does not convey the detailed identity of an invention.").
The function of description requirement is to ensure that the inventor had possession, as of filing date of the application relied on, the specific subject matter claimed by him. See Genentech, 108 F 3d 1361, 1365 (Fed. Cir. at 1366, 78, 1999).
Written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116.
However, a showing of possession alone does not cure the lack of a written description. Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 969-70, 63 USPQ2d 1609, 1617 (Fed. Cir. 2002). For example, it is now well accepted that a satisfactory description may be found in originally-filed claims or any other portion of the originally-filed specification. See In re Koller, 613 F.2d 819, 204 USPQ 702 (CCPA 1980); In re Gardner, 475 F.2d 1389, 177 USPQ 396 (CCPA 1973); In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). However, that does not mean that all originally-filed claims have adequate written support. The specification must still be examined to assess whether an originally-filed claim has adequate written support.
Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods. Where the specification provides only constructive examples in lieu of working examples, it must still "describe the claimed subject matter in terms that establish that the applicant was in possession of the claimed invention, including all of the elements and limitations.
It is suggested to amend the claims to a reasonable genus which is fully described in the specification. To overcome this rejection, incorporate specific agents that are known to be able to be administered with a claimed compound of Formula (I) and list a number of conditions that are contemplated for treatment of those conditions.
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, 30, 31, 37, and 49 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for the compounds set forth in the instant Specification as well as claim 29, e.g., are not considered enabled for the other compounds encompassed by Formula (I) of claim 1. Further, the claims are not enabled for prevention of any disease nor treatment of any condition. Similarly, the claimed compounds are not enabled for the treatment and prevention of the conditions listed in claim 37 to range from traumatic brain injury, AD, PD, ALS, stroke, glaucoma, liver fibrosis, asthma, obesity, lupus, and others. 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 (I), which are alleged by the Specification to act inhibit Factor B, which is thought to be a therapeutic target for a number of conditions which can inhibit the catalytic activity of complement Factor B irrespective of the initial mechanism of activation. See Specification, p3 lines 31-34.
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.”
Shah et al., “Complement system in cancer: friend or foe of immunotherapy,” J Immunother Cancer 2026;14:e013290, teaches the complement system plays a dual role in cancer, influencing tumor suppression and progression.
Further, the role of the complement components is to remove pathogens and damaged cells.
Cazander et al., “Complement Activation and Inhibition in Wound Healing,” Clinical and Developmental Immunology Volume 2012, teaches” “Complement activation is needed to restore tissue injury; however, inappropriate activation of complement, as seen in chronic wounds can cause cell death and enhance inflammation, thus contributing to further injury and impaired wound healing.” Risk factors for chronic wounds that require healing including vascular diseases, diabetes mellitus, and others. See p1, 2nd par.
As discussed above, the instantly claimed invention pertains to compounds of Formula (I), which are alleged by the Specification to act as inhibitors of complement factor B. 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. As noted by Hall et al., “Topological Quantitative Structure–Activity Relationship Applications: Structure Information Representation in Drug Discovery,” Comprehensive Medicinal Chemistry II, Vol 4, 2007, pp537-574, there is a role of structure information representation in drug development. This is based on molecular structure being related to biological activity in structure-activity relationships (QSAR) models. Similarly, structure can be used as a basis to screen a structure library to determine by similarity those that have potential for further development. The basis for this it that structure is correlated to function.
As such, 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 and even bond orientation alone 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 61 compounds on pages 125-137 of the Specification. Table 1 (page 149) provides the efficacy of these compounds in the form of IC50 values for hFactor B TR-FRET. The values for IC50 modulation ranges from less than 0.1 micromolar for “A”, less than 1 micron for “B”, and less than 30 microns for “C”. Thus, the difference in efficacy/potency for A compounds versus C compounds is at least 300 times. Examples 1, 3, 8 and 10 are category A compounds while Examples 2, 4, 6, and 9 are category C compounds. Thus, there is drastic variability with respect to IC50 values for those 61 compounds made and tested.
Despite this variability in efficacy, there is relative commonality among the structures of these synthesized and tested compounds, relative to the instant claims. For example, Examples 1 and 2 (shown below) differ only in bond orientation.
Even further, many of the compounds in Table 1 and the examples have limited structural variability relative to the claims. For example, in most of the synthesized compounds, the following moieties are present:
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or a 5-membered heterocycle with 2-4 nitrogen atoms, CN, or NH2; AND
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, AND
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or a 4-8 membered heterocyclyl.
Despite the single difference being the orientation of a single bond, the IC50 values differ. Thus, even when no atoms are different, the predictability of efficacy is not certain.
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131
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The claimed structural variability is vast relative to the embodiments in the Specification that were made and tested.
Further, the Specification provides no examples of treatment or prevention of any specific condition. Claim 31 is directed to any disease or disorders, and claim 37 include an unsupported laundry list of pathologically disparate conditions.
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 (I), which are alleged by the Specification to as modulate complement factor B. Considering that Formula (I) encompasses potentially tens of thousands of compound species or more, it is evident that the claims are broad. Yet, as discussed above, the instant Specification discloses numerous similarly structured compound species encompassed by Formula (I) as recited by the claims. However, the data provided includes substantial potency variability with respect to IC50 values of those compounds. Further, there are no examples of any treatment or prevention provided in the instant Specification.
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 as inhibitors of complement factor B. 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 (I) with respect to the disclosure and data. 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). Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly 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.
As noted above, there are common structural features among them. For example, in most of the synthesized compounds, the following moieties are present:
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or a 5-membered heterocycle with 2-4 nitrogen atoms, CN, or NH2; AND
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or a 4-8 membered heterocyclyl. Further, a stereoisomer is shown to provide vastly different IC50 potency. See Examples 1-9 and Table 1 on pages 149-151.
Scope or Breadth of the Claims: As stated in MPEP 2164.01(c), “when a compound or Despite this, the instant claims include thousands of permutations and do not require structural limitations that are present in all or substantially all of the structures of the embodiments shown in the Specification.
The above are examples of limited variability among the combinations despite the Specification also showing that minor structural changes can drastically alter the efficacy of a compound.
Not only are the synthesized compounds limited substantially in their structures relative to the breadth of the claims, but the variability and data to any degree is lacking with respect to IC50 hFactor-B TR-FRET data.
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 61 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. This is prior to identifying which subjects can be treated and if any disorder can be prevented. The skilled artisan would then synthesize lead compounds that are within Formula (I) 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 (I) identified by rational drug design based on the instant disclosure would, in fact, be usable. Whether the other compounds of Formula (I) (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 (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.
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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