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 . Claims 1-17 and 19-21 filed February 14, 2025 are currently pending.
Priority
Acknowledgement is made of the national stage entry of PCT/AU22/51575 filed 12/22/2022, which claims foreign priority to Application 2021904204 filed 12/22/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/20/2024, 12/12/2025 and 02/06/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112-Paragraph A-Written Description
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 1-3, 9-16, 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP 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. The courts have stated that, “To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997); In re Gostelli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.” Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co. the court stated that, “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Fiers, 984 F.2d at 1171, 25 USPQ2d 1601; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284985 (CCPA 1973) (“In other cases, particularly but not necessarily, chemical cases, where there is unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus …”) Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that 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 MPEP does state that for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. 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. Although the MPEP does not define what constitute a sufficient number of representative species, the courts have indicated what do not constitute a representative number of species to adequately describe a broad generic. In 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 MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include “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. 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. While all of the factors have been considered, a sufficient amount for a prima facie case are discussed below.
In the present case, the claims are directed to a compound of Formula (X) MLKLi-L-E3L, wherein the E3L is an E3 ligase binding moiety, L is a linker covalently linking MLKLi to E3L and MLKLi is a radical of Formula (I). Formula (X) embraces the unbounded structure of linking the L-E3L moiety to anywhere on the MLKLi of Formula (I).
(1) Partial structure:
Claim 1 recites the structure of MLKLi-L-E3L wherein E3L is an E3 ligase binding moiety, L is a linker covalently linking MLKLi to E3L and MLKLi is a compound of Formula (I). However, the claims do not recite any structural blazemarks to where the L-E3L conjugate is bound to the MLKLi to arrive at Formula (X). In essence, the claims embrace the linker and E3 ligase binding moiety at any chemical substituent of Formula (I). There is no known or disclosed structure/function relationship provided in the claims or the specification, nor blazemarks within the specification to identify which possible linking locations for the L-E3L moiety on to Formula (I) yield efficacious compounds capable of treating necroptosis as recited in the claims. For example, the claims embrace wherein the L-E3L is covalently bound to moieties X, Y, Z, Q1, Q2 R3 and R2 of Formula (I). As described in MPEP § 2163, for a generic claim the genus can be adequately described if the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. However, as shown in claim 17 and the working embodiments, Applicant has only demonstrated working examples wherein the L-E3L motif is specifically linked from the R2 moiety appending the tri-substituted pyrazole core, which does not represent a sufficient number of representative species that encompass the claimed genus.
(2) Physical and/or chemical properties and (3) Functional characteristics: The various elements are described by their function, such as “linker” and “E3 ligase binding moiety”. As recited above, no structure/function relationship is disclosed for the claimed genus providing efficacy when the L-E3L motif is specifically linked to anything other than the R2 moiety appending the tri-substituted pyrazole core.
4) Method of making the claimed invention:
Methods of synthesizing compounds is, in general, known to the artisan, however methods of making the myriad of compounds embraced by functionally claimed genus in the instant claims is beyond the skill of the artisan, particularly when the genus is merely described without any structural blazemarks on where to link the L-E3L moiety to the MLKLi motif of Formula (I). As such, the instant specification and instant claims do not provide sufficient description such that one could arrive at yielding the compounds of the presently claimed genus.
As stated above, the MPEP states that written description for a genus can be achieved by a representative number of species within a broad generic. It is unquestionable that the claims are broad and generic, with respect to all possible compounds encompassed by the claims. The possible structural variations are limitless. Although the claims recite some functional characteristics, the claims lack written description because there is no disclosure of a correlation between function and structure of the compounds beyond those compounds specifically disclosed in the examples in the specification. Moreover, as stated above, the specification lacks sufficient variety of species to reflect this variance in the genus. Thus, the specification does not provide sufficient descriptive support for the myriad of compounds embraced by the claims.
For discussion, Applicant is pointed to Wyeth v. Abbott Laboratories, Nos. 12-1223, 1224 (Fed. Cir. June 26, 2013). In this case the claim was directed towards a specific small molecule, rapamycin (thereby having some actual chemical structure). Yet even when term "rapamycin" (which is much narrower than the genus of MLKLi-L-E3L of Formula (X))) was defined as "a compound containing a macrocyclic triene ring structure produced by Streptomyces hygroscopicus, having immunosuppressive and anti-restenotic effects," the term was found invalid for lack of enablement. Even when the term was accepted to limit the structure to potential rapamycin compounds that should have molecular weights below 1,200 Daltons in order to be permeable across cell membranes. They also found that one of ordinary skill could routinely use the assays disclosed in the specification to determine immunosuppressive and antirestenotic effects in candidate compounds. Yet, the Court found no genuine dispute that practicing the full scope of the claims would require more than routine experimentation for two reasons.
"First, there is no dispute that, even if potential rapamycin compounds must have
a molecular weight below 1,200 Daltons, there are still at least tens of thousands
of candidates. The specification is silent about how to structurally modify sirolimus, let alone in a way that would preserve the recited utility. Second, there is no genuine dispute that it would be necessary to first synthesize and then screen each candidate compound using the assays disclosed in the specification to determine whether it has immunosuppressive and antirestenotic effects. There is no evidence in the record that any particular substitutions outside of the macrocyclic ring are preferable. Indeed, a Wyeth scientist confirmed the unpredictability of the art and the ensuing need to assay each candidate by testifying that, "until you test [compounds], you really can't tell whether they work or not [i.e., have antirestenotic effects]." J.A. 6929. In sum, there is no genuine dispute that practicing the full scope of the claims would require synthesizing and screening each of at least tens of thousands of compounds.
The remaining question is whether having to synthesize and screen each of at
least tens of thousands of candidate compounds constitutes undue experimentation. We hold that it does. Undue experimentation is a matter of degree. Chiron Corp. V. Genentech, Inc., 363 F.3d 1247, 1253 [70 USPQ2d 1321] (Fed. Cir. 2004) (internal quotation omitted). Even "a considerable amount of experimentation is permissible," as long as it is "merely routine" or the specification "provides a reasonable amount of guidance" regarding the direction of experimentation. Johns Hopkins Univ. V. CellPro, Inc., 152 F.3d 1342, 1360-61[47 USPQ2d 1705] (Fed. Cir. 1998) (internal quotation omitted). Yet, routine experimentation is "not without bounds." Cephalon, Inc. V. Watson Pharm., Inc., 707 F.3d 1330, 1339 [105 USPQ2d 1817] (Fed. Cir. 2013)."
While Applicant's claims are rejected under for written description, this case illustrates the scope of Applicants claim to a compound of Formula (X) wherein the linker L and E3 ligase binding moiety are covalently linked to any part of the MLKLi fragment of Formula (I). Applicant has not provided any structural feature for wherein the L-E3L is covalently linked to other parts of MLKLi other than off of R2 motif of Formula (I) (See working examples and claim 17). As discussed above, the unpredictability of the art and the ensuing need to assay each candidate by testifying that, "until you test [compounds], you really can't tell whether they work or not” there is no genuine dispute that practicing the full scope of the claims would require synthesizing and screening each of at least tens of thousands of compounds including wherein the L-E3L is covalently linked to other parts of MLKLi other than off of R2 motif of Formula (I), such as moieties X, Y and Z, which Applicant has not done.
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.
Claim Rejections - 35 USC § 112-Paragraph A-Scope of Enablement
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 20-21 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 treating necroptosis in a subject in need comprising administering a compound of Formula (XI) does not reasonably provide enablement for the treatment of necroptosis in a subject comprising a compound of Formula (X). 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.
Pursuant to In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988), one considers the following factors to determine whether undue experimentation is required: (1) The breadth of the claims, (2) The nature of the invention, (3) The state of the prior art, (4) The level of one of ordinary skill, (5) The level of predictability in the art, (6) The amount of direction provided by the inventor, (7) The existence of working examples, (8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The analysis is as follows:
(1) The breadth of the claims: The breadth of the claims is directed to the treatment of necroptosis in a subject in need comprising administering a compound of Formula (X). The breadth of the claims embraces, compound of Formula (X), wherein the moiety L-EL3 is connected to the mixed lineage kinase inhibitor of Formula (I) at any location on Formula (I).
(2) The nature of the invention: The nature of the invention is treating necroptosis in a subject in need comprising administering a compound of Formula (XI) wherein the L-E3L moiety is distinct conjugated to R2 of Formula (I). See claim 4, claim 17 and the working in-vitro embodiments.
(3): The State of the Prior Art:
The compounds of Formula (I) are neither anticipated in the prior art, nor are there teachings or suggestions to modify the closest prior art compounds of record in order to arrive at the compounds of Formula (I). The closest prior art is as follows:
Lessene (WO2015/172203 published 11/19/2015) teaches treating necroptosis in a subject in need comprising administering a compound that binds to the ATP-binding site of mixed lineage kinase domain-like protein, including compounds of the following genus (claims 1, 11-12).
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Lessene teaches that said compounds bind to murine MLKL domain as demonstrated with surface plasmon resonance technology and inhibited necroptotic death in murine fibroblasts in a dose-dependent manner (page 17, Figure 1). However, Lessene does not provide any working embodiments of MLK inhibitors in-vivo working embodiments to enable this claim, let alone the disease states embraced in claim 21, nor demonstrate that compounds of Formula (X) are efficacious at treating necroptosis.
Jalan (WO2019/180451 published 09/26/2019) teaches treating necroptosis. Jalan teaches that necroptosis is a form of non-apoptotic programmed cell death that results in the release of pro-inflammatory cell contents that can further trigger inflammation, accelerating further cell death and organ failure. RIPK1 and RIPK3 are known to be central to the necroptotic pathway as RIPK1 forms an intercellular complex with RIPK3 to assemble the necrosome. Downstream of RIPK3 is mixed-lineage kinase domain-like protein (MLKL), a pseudokinase that, once phosphorylated, causes necroptosis (page 2 lines 1-10). Jalan further teaches antagonists of MLKL are efficacious for treating aberrant necroptosis in a subject (claim 1, 18). However, Jalan does not provide any working embodiments of MLK inhibitors nor in-vitro nor in-vivo working embodiments to enable this claim, let alone compounds of Formula (X).
Given that the state of the prior art discloses that mixed lineage kinase inhibitors are efficacious at treating necroptosis in a subject in need without demonstrating any capacity to do so in an in-vivo working model, one of ordinary skill in the art would not accept on its face Applicant's statement that the treatment of necroptosis could be achieved with the presently claimed compound of Formula (X), especially considering the fact that compounds that embrace the moiety L-EL3 appending any substituent of Formula (I) other than R2 had not been reduced to practice.
In other words, the artisan would have required sufficient direction as to how the administration of the presently claimed active agent(s) of Formula (X) could actually treat the subject with necroptosis that the artisan would have been imbued with at least a reasonable expectation of success. Such success would not have been reasonably expected given that the concept that efficacy in in-vitro models does not necessarily lead to in-vivo efficacy and, thus, met with a great deal of skepticism.
(4) The level of one of ordinary skill: The level of skill in the art is high and is at least that of a medical doctor with several years of experience in the art of treating necroptosis.
(5) The level of predictability in the art:
The level of predictability in the art is low given that the state of the prior art teaches treatment of necroptosis in a subject comprising administering a mixed-lineage kinase inhibitor, without any physical data demonstrating efficacy.
(6) The amount of direction provided by the inventor and (7) The existence of working examples:
Applicant solely provides in-vitro analysis of compounds of Formula (X) wherein the linker and E3 ligase binder is conjugated specifically to R2 of Formula (I), and their capacity to bind to full length mixed lineage kinase, or inhibit necroptosis in U937 leukemia cells (pages 441-461). As shown in Table 37, many of the compounds embodied in Formula (X) comprise no selectivity between an off-target effect and the inhibition of TSQ-induced necroptosis. Applicant also does not provide an in-vivo working embodiment demonstrating the capacity of the compounds of Formula (X) to treat necroptosis in a subject in need, let alone in any of the disease states embraced within claim 21, or wherein the L-E3L motif is located other than off of R2 on Formula (I).
In light of the fact that the specification fails to provide the skilled artisan with any direction or guidance as to how the treatment of necroptosis could actually be achieved without a working example, the present specification is viewed as lacking an enabling disclosure of the entire scope of the claimed invention and requiring an undue level of experimentation for this aspect of the invention.
(8) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
The basis for the present rejection is not simply that experimentation would be required, since it is clear from the state of the prior art and Applicant's disclosure that experimentation in this particular art is not at all uncommon, but that the experimentation required in order to practice this aspect of the invention would be undue. Please reference In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976), which states, "The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue." (emphasis added) Applicant fails to address the unpredictability in the art by providing adequate direction or guidance as to how to practice this aspect of the invention, in terms of disclosing how to use the presently claimed compounds of Formula (X) such that treating necroptosis could be reasonably achieved in a subject, or even any basis for extrapolating the in-vitro mixed lineage kinase antagonist activity results shown in the working embodiments. As a result, the specification is viewed as lacking an enabling disclosure of the same.
Claim Rejections - 35 USC § 112-Paragraph B
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 9-10 are 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.
Claims 9-10 recite the phrase “or an E3 ligase binding derivative thereof”. The term is indefinite as the phrase “an E3 ligase binding derivate” is described by its function and not its structure. Applicant has failed to identify structural blazemarks as to which chemical moieties are required for a composition to read on an E3 ligase binding derivate, and which compounds lie outside of the purported genus.
Without providing some guidance to structure, this term is relative and indefinite and without ANY structure. Moreover, MPEP 2703.05(g) states that the use of functional language in a claim may fail "to provide a clear-cut indication of the scope of the subject matter embraced by the claim" and thus be indefinite. In re Swinehart, 439 F.2d 210, 213 (CCPA 1971). For example, when claims merely recite a description of a problem to be solved or a function or result achieved by the invention, the boundaries of the claim scope may be unclear. Halliburton Energy Servs., Inc. v.M-ILLC, 514 F.3d 1244, 1255, 85 USPQ2d 1654, 1663 (Fed. Cir. 2008) (noting that the Supreme Court explained that a vice of functional claiming occurs "when the inventor is painstaking when he recites what has already been seen, and then uses conveniently functional
language at the exact point of novelty") (quoting General Elec. Co. V. Wabash Appliance Corp., 304 U.S. 364, 371 (1938)); see also United Carbon Co. V. Binney & Smith Co., 317 U.S. 228, 234 (1942) (holding indefinite claims that recited substantially pure carbon black "in the form of commercially uniform, comparatively small, rounded smooth aggregates having a spongy or porous exterior"). Further, without reciting the particular structure, materials or steps that accomplish the function or achieve the result, all means or methods of resolving the problem may be encompassed by the claim. Ariad Pharmaceuticals., Inc. V. Eli Lilly & Co., 598 F.3d 1336, 1353, 94 USPQ2d 1161, 1173 (Fed. Cir. 2010) (en banc).
Accordingly, one of ordinary skill in the art prior to the time of the invention would not have been readily apprised of the metes and bounds of the subject matter for which Applicant was presently seeking protection.
Conclusion
Claims 1-3, 9-16 and 20-21 are rejected. Claims 4-8 and 17 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GEORGE W KOSTURKO whose telephone number is (571)270-5903. The examiner can normally be reached M-F 9:00-5:30.
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/GEORGE W KOSTURKO/Primary Examiner, Art Unit 1621
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