DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
2. Applicant's election without traverse of Group I (claims 1, 3, 5, and 8-9) and species: IL-1 β mutant Q148G in the reply filed on April 2, 2026 is acknowledged. Therefore, claims: 1, 3, 5-9, and 14-15 are presently pending; claims 6-7 and 14-15 are presently withdrawn; and claims 1, 3, 5, and 8-9 are presently subject to examination. Applicant did not specifically elect a species that is recited in claim 1. For the purposes of examination, the examiner is examining Q148X to read on Q148G. See the rejection under 112(b) below.
Information Disclosure Statement
3. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
The references should be placed on an information disclosure statement if Applicant would like them considered.
Objection to the Specification
4. The instant specification is objected to for the following reasons:
a. There are trademarks in this application that do not meet the requirements.
The use of the term (e.g., “Olympus,” “Alexa,” and “Fluoview” at pg. 11, 1st para.), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks. Please, review the specification for other improper trademarks and correction is required.
b. Nucleotide and/or amino acid sequences appearing in the specification (i.e., at Table 1) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers is requested, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
c. There are also what appears to be claims under an additional claims section at pg. 20; if they are claims they should be placed on a separate page.
Double Patenting
5. 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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/proces/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 3, 5, and 8-9 are rejected on the grounds of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 9,932,409, filed January 15, 2016. In light of US9492562B2, published November 15, 2016. Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons:
The instant claims are directed to a targeting construct, comprising a modified IL-1 family cytokine characterized by a reduced affinity for its receptor, and a targeting moiety, wherein the modified IL-1 family cytokine is an IL-1 β mutant (Q148G). The targeting moiety may target a marker expressed on a IL-1 family cytokine receptor expressing cell. The targeting moiety may target to a marker expressed on an IL-1R1 and/or IL-1RacP expressing cell. The targeting moiety may be an antibody. The antibody may be a VHH.
The reference claims are directed to a composition comprising a fusion protein comprising a mutated human IL-1 β cytokine characterized by a reduced activity as compared to wild type human IL-1 β cytokine, wherein the mutation is selected from a list including Q148G, and a targeting moiety comprising a variable domain of VHH, wherein the targeting moiety restores activity of the mutated human IL-1 β cytokine on target cell (see e.g., claim 1). The targeting moiety may be by directed to a marker expressed on human IL-1 β cytokine receptor expressing cell (see e.g., claim 2). The targeting may be directed to a marker expressed on a IL-1R1 and/or IL-1RacP expressing cell (see e.g., claim 3). The mutated human IL-1 β may be characterized by a reduced affinity for its receptor as compared to a wild type human IL-1 β cytokine (see e.g., claim 4).
The reference patent claims anticipate the instant claims, but the reference patent claims differ in scope from the instant claims because the reference patent claims require “a composition comprising the fusion protein” and “wherein the targeting moiety restores activity of the mutated human IL-1 β,” which are not required in the instant claims. In light of US9492562B2, published November 15, 2016, at Col. 4, ln. 63-64, a targeting construct may be a fusion protein, and therefore the first limitation differs in requiring the fusion protein / targeting construct to be comprised in a composition. Therefore, the reference patent claims recite species encompassed by the instant claimed genus targeting constructs, thereby anticipating the invention of the instant claims, but the reference claimed genus is not identical to the instant claimed genus. Therefore, the conflicting claims are not patentably distinct from each other.
Claim Rejections - 35 USC § 112
6. 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.
Written Description
7. Claims 1, 3, 5, and 8-9 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 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 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. 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.”
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that:
"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. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
No Written Description for the Breath of the Claims (“targeting moiety” targeting “markers”):
The claims are directed to a targeting construct comprising mutant IL-1 β cytokine and a “targeting moiety.” The claims recite that the targeting moiety targets a “maker” expressed on an IL-1 expressing cell (e.g., claim 3). The claims therefore broadly encompass that the targeting construct can have any “targeting moiety” that targets a respective “marker.” However, there is no structure recited in the claims that would correlate with these functions. The specification only sets forth targeting constructs having Her2 or mLR VHH “targeting moiety” targeting Her2 or mLR “markers” artificially overexpressed on the cell membrane (see Example 2, the only non-prophetic example in the specification) as potentially having the required targeting function. Furthermore, the targeting molecule included a specific linker not recited in the claims. However, these two targeting constructs are not sufficiently representative of such a broad genus of “targeting moiety” and “markers” as instantly claimed.
The specification only discloses the effects of two “targeting constructs” having reduced-affinity IL-1 β mutants: human IL-1 β mutants fused to (i) a VHH nanobody (i.e., “targeting moiety”) recognizing Her2 (1R59B) (i.e., “marker”) by a 13 x GGS linker; and (ii) a VHH nanobody recognizing murine leptin receptor (mLR; 4-10) by the same 13 x GGS linker, both at Example 2 (note: Examples 3-7 are prophetic and do not specifically disclose additional targeting constructs). These two targeting constructs are tested with HEK-Blue IL-1 β cells (i.e., expressing IL-1 receptor) transfected by calcium phosphate technique with Her2 or mLR expression plasmids, to overexpress Her2 or mLR “markers” respectively. Effects on NF-kB activation is shown in FIGs. 2-5.
The claims recite functional language of the targeting construct, such as “targeting” the marker; however, a definition by function does not suffice to define the genus because it is only an indication of what the targeting construct does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of targeting constructs is highly variable (e.g., targeting construct would necessarily have unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed “targeting moieties” that target “markers” have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of cytokine targeting constructs is provided below, which shows that the genus “targeting moiety” is highly variable with respect to making a targeting construct, and is heavily dependent on the choice of targeting moiety; and the linker connecting targeting moiety to cytokine.
The state of the art indicates it is very unpredictable how well targeting constructs, e.g., the VHH-cytokine fusion proteins encompassed by the claims, will target the targeting construct to a marker proximal to cytokine receptor, thereby permitting the targeting construct’s cytokine to bind to cytokine receptor and induce “activation by targeting.” See e.g., instant Example 2 for discussion of the “activation by targeting” concept, whereby the targeting construct performs targeted activation of cytokine receptors to produce localized effects of the cytokine and reduce systemic effects of the cytokine. This unpredictability stems from the relationship between (i) the choice of marker, e.g., the abundance of the cell-surface marker (e.g., Her2) to perform initial targeting of the targeting construct towards cytokine receptors; (ii) linker design, which controls the radius by which a marker-bound targeting construct’s cytokine may interact with cytokine receptor and thereby effectuate activation of the cytokine, and (iii) the binding kinetics of the targeting construct’s targeting moiety to marker; and cytokine (e.g., human vs unspecified IL-1 β) to cytokine receptor, which affects whether or not targeted activation of a cytokine receptor will be obtained.
Robinson-Mosher et al. ("Designing cell-targeted therapeutic proteins reveals the interplay between domain connectivity and cell binding." Biophysical Journal 107.10 (2014): 2456-2466.) is directed to targeted cell delivery of cytokines by tethering cytokines to antibodies to target reduce side effects of cytokine therapeutics (see the abstract). Robinson-Mosher et al. is concerned with the geometric configuration and relative binding affinities of targeting moiety and cytokine to achieve desired level of cell-targeted binding and activity, and addresses design issues with a model that varies the linker length. Id.
Robinson-Mosher et al. teaches: “Mutating the cytokine to weaken its binding affinity reduces its activity on all cell types, whereas fusing it to an antibody rescues its activity only on cell types that express the antibody’s target by increasing its effective local concentration. For targeting to be effective, the antibody’s affinity should be substantially higher than the cytokine’s.” Robinson-Mosher et al. at pg. 2457, left col. Therefore, the targeting moiety must be selected to have significantly higher affinity to marker than cytokine for cytokine receptor.
Robinson-Mosher et al. further teaches: “The activity of an antibody-cytokine chimera is also regulated by its geometric configuration. The domains must be arranged in a spatial configuration that allows the appropriate protein-protein interactions. The geometric configuration of an antibody-cytokine fusion can be modulated by modifying the linker between the two protein domains. The length and flexibility of the linker have a significant impact on the accessibility of the antibody and cytokine to their respective binding targets. For example, a sufficient separation between the two protein domains is necessary for optimal fusion protein activity. Moreover, rigid linkers often result in better protein domain separation and fusion protein activity compared with flexible linkers.” Id. Therefore, the length and rigidity of the linker between the targeting moiety and cytokine are important considerations to produce a targeting construct that sufficiently targets the cytokine of the targeting construct to cytokine receptor.
Robinson-Mosher et al. at FIG. 3, reproduced below for Applicant’s convenience, shows that linker length affects the likelihood that the targeting construct’s cytokine will reach and therefore bind cytokine receptor by the swept volume of the cytokine. Therefore, the surface-abundance of the marker the targeting construct binds to will also affect the likelihood a cytokine receptor will be in the swept volume of the targeting construct’s cytokine since a lower abundance marker will necessarily place fewer cytokine receptors within the swept volume, and vice versa.
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Robinson-Mosher et al. at FIG. 4A, reproduced below for Applicant’s convenience, also shows that the shortest linker tested (15 bp) resulted in superior targeting of a reduced-activity IFNα / CD20+ targeting construct, but increased off-target effects, and vice versa for the longest linker tested (45 bp). Robinson-Mosher et al. notes that “signaling enhancement decreased as the linker length increased” at pg. 2461, right col. Therefore, linker length must be optimized to balance target effects with off-target effects to produce a “targeting construct” that achieves targeting by activation.
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Robinson-Mosher et al. concludes: “Ideally, targeted antibody-cytokine fusions designed for simultaneous binding of both antibody and cytokine to the same target cell should be driven by the antibody element, but the on-rates and affinities of antibodies and nonmutant cytokines are often similar. This complex 3D dynamic process requires coordination of the spatial configuration and binding affinity of the protein domains.” Robinson-Mosher et al. at discussion pg. 2463, right col. In other words, substantial optimization of selected cytokine, targeting moiety, and linker are required to produce a functional “targeting construct.”
This need for optimization is corroborated by Fabilane et al. ("Cytokine/antibody fusion protein design and evaluation." Current protocols 4.5 (2024): e1061.), also directed to cytokine/antibody design considerations. Fabilane et al. provides a troubleshooting guide at Table 1, and explicitly teaches that a possible cause of failure to achieve intramolecular assembly of the targeting construct is a linker that is too long or short or having suboptimal composition, and provides the solution of varying the linker length and composition until correct assembly is achieved.
Therefore, without actually performing the required experiments, it is unpredictable which members of the instantly claimed genus of “targeting construct” comprising: Q148G reduced affinity IL-1 β mutants (from any species), “targeting moiety” for “markers”, and not requiring a linker; will effectively function as a “targeting construct” and thereby target the cytokine to cytokine receptor by the targeting moiety to achieve activation by targeting.
Neither the art nor the specification provides a sufficient representative number of “targeting moieties” species that target “markers” to meet the written description requirement for instant claims directed to IL-1 β mutant targeting constructs in general.
It is therefore unknown how the instantly claimed genus of targeting constructs would target the markers whilst permitting the simultaneous binding of marker and IL-1 β receptor to be considered a “targeting construct.” Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of “targeting moiety” and “marker” encompassed by the claims—especially given the claims omit the required linker to allow the simultaneous binding of cytokine receptor and marker. Given all of the above, Applicant does not have written description for a targeting construct comprising a general “targeting moiety” that targets “marker.”
No Written Description for the Breath of the Claims (“IL-1 β mutant” characterized by reduced affinity for “its receptor”):
The claims further recite that the “IL-1 β mutant” is characterized by reduced affinity for “its receptor.” The claims do not specify what species the IL-1 β mutant originates from, nor what receptor the IL-1 β mutant must have reduced affinity for. The claims therefore encompass any Q148G IL-1 β mutant that has reduced affinity for any of its receptors.
The specification indicates that only human IL-1 β mutants were used at FIG. 1, and that they were tested in HEK-Blue cells specifically expressing the IL-1R receptor.
The claims recite functional language of the IL-1 β mutant, such as that it is characterized by a reduced affinity for its receptor; however, a definition by function does not suffice to define the genus because it is only an indication of what the IL-1 β mutant does, rather than what it is; therefore, it is only a definition of a useful result rather than a definition of what achieves that result. In addition, because the genus of IL-1 β mutants is highly variable (e.g., IL-1 β mutant from a different species would necessarily have unique structure), the generic description of the substance is insufficient to describe the genus. Thus, the encompassed “IL-1 β mutants” from unspecified species have no correlation between their structure and function. To address this issue, a brief assessment of the state of the art of IL-1 β is provided below, which shows that the genus is highly variable with respect to species of origin, and also that there exists multiple receptor types a given IL-1 β may bind to, and therefore there is no single receptor an IL-1 β may have “reduced affinity” towards, as encompassed by the claims.
Bird et al. (“Evolution of interleukin-1β” Cytokine & Growth Factor Reviews, Volume 13, Issue 6, 2002, pg 483-502) is a survey of the evolution to IL-1 β. Bird et al. teaches “Although the IL-1 sequences share the IL-1 family sig nature and show the presence of possible-sheets the overall nucleotide and amino acid identities of these molecules within vertebrates is quite low” and points to FIG. 2, showing the low identity between species. Bird et al. also highlights the existence of IL-1 type II decoy receptors at section 8. Accordingly, it is unknown how a IL-1 β from any species will respond to a Q148G mutation and reduce affinity, and for what receptor.
Neither the art nor the specification provides a sufficient representative number of “IL-1 β” with reduced affinity for “its receptor” in general to meet the written description requirement for instant claims directed to targeting constructs having any IL-1 β mutated Q148G and having reduced affinity for “its receptor.”
It is therefore unknown how the genus of a “IL-1 β” Q148G mutants would bind with reduced affinity to “its receptor.” Applicant has not shown possession of a representative number of species that have the claimed function(s). The specification therefore provides insufficient written description to support the genus of IL-1 β mutants encompassed by the claims.
Given all of the above, the cited reference therefore demonstrate that Applicant is not in possession of: a targeting construct comprising “IL-2 β” Q148G mutant having reduced affinity for its receptor, and “targeting moiety” targeting “markers.” Applicant is in possession of: a targeting construct comprising “human IL-1 β” Q148G mutant, having reduced affinity for IL1-R1, and linked with specific GS linker to Her2 or mLR VHH targeting overexpressed Her2 or mLR markers.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow person of ordinary skill in the art to recognize that he or she invented what is claimed’”. The courts have decided: the purpose of the "written description" requirement is broader than to merely explain how to "make and use"; the 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. The invention is for purposes of the “written description” inquiry, whatever is now claimed. See Vas-Cath, Inc v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Federal Circuit, 1991).
Furthermore, the written description provision of 35 USC §112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993). And Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. Moreover, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. However, factual evidence of an actual reduction to practice has not been disclosed by Applicant in the specification; nor has Applicant shown the invention was “ready for patenting” by disclosure of drawings or structural chemical formulas that show that the invention was complete; nor has the Applicant described distinguishing identifying characteristics sufficient to show that Applicant were in possession of the claimed invention at the time the application was filed.
Therefore, for all these reasons the specification lacks adequate written description, and one of skill in the art cannot reasonably conclude that Applicant had possession of the claimed invention at the time the instant application was filed.
Enablement
8. Claims 1, 3, 5, and 8-9 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 targeting construct targeting overexpressed Her2 or leptin receptor (mLR), the targeting construct having reduced affinity human IL-1 β mutant Q148G fused to VHH targeting Her2 or mLR by a 13 x GGS linker, does not reasonably provide enablement for a targeting construct comprising reduced affinity IL-1 β mutant Q148G “and a targeting moiety” targeting “markers” in general. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
It is noted that MPEP 2164.03 teaches that “the amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The amount of guidance or direction refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as how to make and use the invention in order to be enabling.”
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 most recently in 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). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
Enablement is considered in view of the Wands factors (MPEP 2164.01 (A)). The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)):
1) nature of the invention;
2) the breadth of the claims;
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 or guidance provided by the inventor;
7) the existence of working examples; and
8) the quantity of experimentation needed to make or use the invention based on the content of the disclosure.
When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(2) The breadth of the claims:
The claims are drawn to targeting constructs comprising reduced affinity IL-1 β mutant: Q148G (the IL-1 β being from any species) and a “targeting moiety.” The claims characterize the IL-1 β mutant by having reduced affinity for its receptor without specifying the receptor. The claims recite that the “targeting moiety” of the targeting construct targets “markers” expressed on IL-1 receptor expressing cells, but does not identify what the markers are (i.e., claims 3, 5); and that the targeting moiety may be an antibody or VHH antibody in general, without further specifying what markers the antibody / VHH antibody binds to (i.e., claims 8-9). Further, the claims do not recite any structure linking the IL-1 β mutant to the targeting moiety, i.e., the linker (see FIG. 1).
Claims 1, 3, 5, and 8-9 are therefore broad and encompass targeting constructs comprising a reduced affinity IL-1 β mutant from any species having mutation Q148G and any “targeting moiety” that targets any “marker” (i.e., all markers—not only the exemplified Her2 or mLR markers) and that the IL-1 β mutant and targeting moiety may be linked to form the targeting construct by any means whatsoever.
(5) The predictability or unpredictability of the art:
The state of the art indicates it is very unpredictable how well targeting constructs, e.g., the antibody-cytokine fusion proteins encompassed by the claims, will target the targeting construct to a marker proximal to cytokine receptor, thereby enabling the targeting construct’s cytokine to bind to cytokine receptor and induce “activation by targeting.” See e.g., instant Example 2 for discussion of the “activation by targeting” concept, whereby the targeting construct performs targeted activation of cytokine receptors to produce localized effects of the cytokine and reduce systemic effects of the cytokine. This unpredictability stems from the relationship between (i) the choice of marker, e.g., the abundance of the cell-surface marker (e.g., Her2) to perform initial targeting of the targeting construct towards cytokine receptors; (ii) linker design, which controls the radius by which a marker-bound targeting construct’s cytokine may interact with cytokine receptor and thereby effectuate activation of the cytokine, and (iii) the binding kinetics of the targeting construct’s targeting moiety to marker; and cytokine (e.g., human vs unspecified IL-1 β) to cytokine receptor, which affects whether or not targeted activation of a cytokine receptor will be obtained.
Robinson-Mosher et al. ("Designing cell-targeted therapeutic proteins reveals the interplay between domain connectivity and cell binding." Biophysical Journal 107.10 (2014): 2456-2466.) is directed to targeted cell delivery of cytokines by tethering cytokines to antibodies to target reduce side effects of cytokine therapeutics (see the abstract). Robinson-Mosher et al. is concerned with the geometric configuration and relative binding affinities of targeting moiety and cytokine to achieve desired level of cell-targeted binding and activity, and addresses design issues with a model that varies the linker length. Id.
Robinson-Mosher et al. teaches: “Mutating the cytokine to weaken its binding affinity reduces its activity on all cell types, whereas fusing it to an antibody rescues its activity only on cell types that express the antibody’s target by increasing its effective local concentration. For targeting to be effective, the antibody’s affinity should be substantially higher than the cytokine’s.” Robinson-Mosher et al. at pg. 2457, left col. Therefore, the targeting moiety must be selected to have significantly higher affinity to marker than cytokine for cytokine receptor.
Robinson-Mosher et al. further teaches: “The activity of an antibody-cytokine chimera is also regulated by its geometric configuration. The domains must be arranged in a spatial configuration that allows the appropriate protein-protein interactions. The geometric configuration of an antibody-cytokine fusion can be modulated by modifying the linker between the two protein domains. The length and flexibility of the linker have a significant impact on the accessibility of the antibody and cytokine to their respective binding targets. For example, a sufficient separation between the two protein domains is necessary for optimal fusion protein activity. Moreover, rigid linkers often result in better protein domain separation and fusion protein activity compared with flexible linkers.” Id. Therefore, the length and rigidity of the linker between the targeting moiety and cytokine are important considerations to produce a targeting construct that sufficiently targets the cytokine of the targeting construct to cytokine receptor.
Robinson-Mosher et al. at FIG. 3, reproduced below for Applicant’s convenience, shows that linker length affects the likelihood that the targeting construct’s cytokine will reach and therefore bind cytokine receptor by the swept volume of the cytokine. Therefore, the surface-abundance of the marker the targeting construct binds to will also affect the likelihood a cytokine receptor will be in the swept volume of the targeting construct’s cytokine since a lower abundance marker will necessarily place fewer cytokine receptors within the swept volume, and vice versa.
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Robinson-Mosher et al. at FIG. 4A, reproduced below for Applicant’s convenience, also shows that the shortest linker tested (15 bp) resulted in superior targeting of a reduced-activity IFNα / CD20+ targeting construct, but increased off-target effects, and vice versa for the longest linker tested (45 bp). Robinson-Mosher et al. notes that “signaling enhancement decreased as the linker length increased” at pg. 2461, right col. Therefore, linker length must be optimized to balance target effects with off-target effects to produce a “targeting construct” that achieves targeting by activation.
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Robinson-Mosher et al. concludes: “Ideally, targeted antibody-cytokine fusions designed for simultaneous binding of both antibody and cytokine to the same target cell should be driven by the antibody element, but the on-rates and affinities of antibodies and nonmutant cytokines are often similar. This complex 3D dynamic process requires coordination of the spatial configuration and binding affinity of the protein domains.” Robinson-Mosher et al. at discussion pg. 2463, right col. In other words, substantial optimization of selected cytokine, targeting moiety, and linker are required to produce a functional “targeting construct.”
This need for optimization is corroborated by Fabilane et al. ("Cytokine/antibody fusion protein design and evaluation." Current protocols 4.5 (2024): e1061.), also directed to cytokine/antibody design considerations. Fabilane et al. provides a troubleshooting guide at Table 1, and explicitly teaches that a possible cause of failure to achieve intramolecular assembly of the targeting construct is a linker that is too long or short or having suboptimal composition, and provides the solution of varying the linker length and composition until correct assembly is achieved.
Therefore, without actually performing the required experiments, it is unpredictable which members of the instantly claimed genus of “targeting construct” comprising: Q148G reduced affinity IL-1 β mutants (from any species), “targeting moiety” for “markers”, and not requiring a linker; will effectively function as a “targeting construct” and thereby target the cytokine to cytokine receptor by the targeting moiety to achieve activation by targeting.
6) the amount of direction or guidance provided by the inventor:
The specification only discloses the effects of two “targeting constructs” having reduced-affinity IL-1 β mutants: human IL-1 β mutants fused to (i) a nanobody (i.e., “targeting moiety”) recognizing Her2 (1R59B) (i.e., “marker”) by a 13 x GGS linker; and (ii) a nanobody recognizing murine leptin receptor (mLR; 4-10) by the same 13 x GGS linker, both at Example 2 (note: Examples 3-7 are prophetic and do not specifically disclose additional targeting constructs). These two targeting constructs are tested with HEK-Blue IL-1 β cells (i.e., expressing IL-1 receptor) transfected by calcium phosphate technique with Her2 or mLR expression plasmids, to overexpress Her2 or mLR “markers” respectively. Effects on NF-kB activation is shown in FIGs. 2-5.
Accordingly, the specification only discloses the effects of human IL-1 β mutants fused to two nanobodies by a specific 13 x GGS linker, and further only shows the effects obtained with these two targeting constructs in HEK-Blue IL-1 β cells overexpressing the target / marker for the respective nanobody (i.e., Her2 or mLR). The level of cell-surface co-expression of the IL-1 receptor with Her2 / mLR marker is not determined or shown, and therefore it is unknown how densely the cytokine receptor and marker were co-expressed at the HEK cell surface. It is therefore unknown how the two targeting constructs detailed in the specification would achieve activation by targeting—which requires the cytokine and targeting moieties of the targeting construct to bind a cytokine receptor and marker on the cell surface simultaneously—in any cell other than the specific HEK cell line transfected with the specific markers complementary to the two nanobodies detailed in the specification.
Given the evidence above, one of skill in the art could not reasonably extrapolate the instant findings regarding the two disclosed targeting constructs (i.e., having nanobodies targeting overexpressed markers and a specific linker) to the breadth of the claim-recited targeting constructs—having “targeting moieties” against “makers” in general, and not requiring a linker. It would be undue experimentation to determine what targeting moieties, targeting which markers, and linked by what means to which reduced-affinity IL-1 β mutants comprising Q148G mutation, would result in activation by targeting, and therefore be considered a “targeting construct.”
8) the quantity of experimentation needed to make or use the invention:
It would be undue experimentation to make or use the invention encompassed by the breadth of the claims because the Q148G IL-1 β mutants from various species would need to be fused to each “targeting moiety” targeting a “marker” by some kind of linker, the linker further optimized until activation by targeting was achieved for a target cell co-expressing IL-1 receptor and the marker. As discussed above, the linker will affect the activity of the targeting construct, and is also dependent on the variable of the marker selected, and how highly co-expressed the marker is with IL-1 receptor to facilitate the simultaneous binding of the targeting construct’s cytokine moiety (whose affinity for the cytokine receptor will vary depending on the species of origin of the IL-1 β) and targeting moiety to: cytokine receptor and marker, respectively, to achieve activation by targeting and therefore be a “targeting construct.” Each of the claim-recited targeting constructs having different IL-1 β and targeting moieties / markers would need to be generated, retested, and the linkers optimized to achieve the “targeting construct.” Applicant has only demonstrated targeting constructs having reduced affinity human IL-1 β comprising Q148G mutation, nanobodies targeting Her2 and mLR, and a specific linker—and importantly, which targets a cell line overexpressing both IL-1 receptor and Her2 or mLR. Robinson-Mosher et al. shows it is very unpredictable how the instantly demonstrated linker (or no linker at all as instantly claimed), will work to create a targeting construct having unspecified targeting moieties against unspecified markers because at least the density of the IL-1 receptor and the marker will vary depending on the cell type, and so without performing the experiments, it is unknow how the targeting constructs will bind to both IL-1 receptor and marker simultaneously to effectuate activation by targeting.
In conclusion, the claimed invention does not provide enablement for a targeting construct comprising reduced affinity IL-1 β mutant Q148G “and a targeting moiety” targeting “markers” in general. The claimed invention only provides enablement for the species “Her2” and “mLR” VHH targeting moieties, linked to the Q148G human IL-1 β mutant via 13 x GGS linker, and further targeting a cell overexpressing Her2 or mLR markers. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
9. 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.
a. Claims 1, 3, 5, and 8-9 under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 1 recites that the cytokine is “characterized by” a reduced affinity for its receptor. The term “characterized by” is not defined in the specification; it is unclear if “characterized by” means the characterized feature is an essential characteristic of the cytokine, or merely an ancillary feature of the cytokine. Do the claims require the cytokine to have reduced affinity for its receptor? Appropriate clarification and/or correction is requested.
b. Claims 1, 3, 5, and 8-9 under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 1 recites that the cytokine is characterized by a “reduced affinity” for its receptor. The term “reduced” is not defined in the specification; the term “reduced” is a term of degree that renders the claim indefinite because it is unclear how much reduction of affinity is required to fall within the scope of the claims. Does a targeting construct having cytokine with 0.1% reduced affinity for its receptor fall within the scope of the claims? And reduced affinity for which of its receptors (i.e., IL-1R1 or IL-1RII)? Appropriate clarification and/or correction is requested.
c. Claims 1, 3, 5, and 8-9 under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 1 recites “wherein the modified IL-1 family cytokine is an IL-1 β mutant, selected from the group consisting of A117G/P118G, R120G/R120X, L122A, T125G/L126G, R127G, Q130X, 0131G, K132A, S137GlQ138Y, L145G, H146X, L145AIL147A, Q148X, Q148G/Q150G, Q150G/D151A, M152G, F162A, F162A/Q164E, F166A, Q164E/E167K, N169G/D170G, 1172A, V174A, K208E, K209A, K209X, K209AIK210A, K219X, and E221KX, E221S/N224A, N224S/K225S, E244K and N245Q.” The claim does not require the IL-1 β mutant be from a particular species, and therefore it is unclear how the recited point mutants map to the various IL-1 β cytokines encompassed by the claims. Additionally, the claims do not recite the elected species: Q148G. Appropriate clarification and/or correction is requested.
d. Claims 9 is rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor regards as the invention.
Claim 9 recites: “wherein said antibody is a variable domain of heavy chain antibody (VHH).” The specification at pg. 5, lines 20-21 describes (VHH) as: “variable domain of camelid heavy chain antibodies.” It is thus unclear if the “VHH” recited in the claims differs the VHH cited in the specification. Is there any difference between the two VHH abbreviations? Appropriate clarification and/or correction is requested.
Conclusion
10. No claim is allowed.
11. Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON R SCHWECHTER whose telephone number is (571)272-1270. The examiner can normally be reached M-Th 7-5 EST.
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/BRANDON R SCHWECHTER/
Examiner, Art Unit 1674
/VANESSA L. FORD/ Supervisory Patent Examiner, Art Unit 1674
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