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 .
Detailed Action
Election Response
The response filed on 8/18/2025 to the restriction requirement of 6/20/2025 has been received. Applicant has elected Group II, claims 2-20 for examination, and the species (a) that the agent capable of inhibiting CLEVER-1 expression is an antibody (relevant to claims 2 and 3), (b) that the agent capable of inhibiting CLEVER-1 expression or capable of binding to CLEVER-1 is administered prior to administration of inhibitor of interleukin and/or inhibitor of respective interleukin receptors; (c) the method further comprises an agent capable of binding to IFNAR, (claim 6) and (d) inhibitor of interleukin and/or inhibitor of respective interleukin receptors is administered simultaneously with an agent capable of binding IFNAR (claim 10; withdraw claim 11)
Because Applicant did not distinctly and specifically point out any errors in the restriction requirement, the election has been treated as an election without traverse (MPEP 818.03(a)). Claims 2-20 are pending. Claims 8 and 11 are withdrawn as being drawn to non-elected species. Claims 2-7, 9, 10, and 12-20 are currently under prosecution.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 2-7, 9, 10, and 12-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature/ a natural phenomenon) without significantly more.
Examiner provides the USPTO’s analysis below:
Step 1: Is the claim directed to a process, machine, manufacture or composition of matter?
Yes, the claims are drawn to a process.
Step 2A(1): Does the claim recite a law of nature, natural phenomenon, product of nature, or abstract idea?
The claims are drawn to a natural phenomenon and an abstract idea. The clams are drawn to a method for monitoring a patient’s response to anti-CLEVER-1 therapy and evaluating the need for combination therapy comprising an inhibitor of interleukin and/or the respective interleukin receptor, when an agent binding capable of binding to CLEVER-1 has been administered to the patient, the method comprising: (1) obtaining a sample from the patient at a first point in time prior to the administration of the agent capable of binding to CLEVER-1 to a patient, (2) obtaining a sample from the patient at a later time point in time after the administration of an agent capable of binding to CELVER-1 to a patient, (3) measuring a level of interleukin IL-1, IL-6, and/or IL-8 from the obtained samples, and (4) comparing the levels of IL-1, IL-6 and/or IL8 measured from the sample obtained at a later point of time of the expression level compared to the first point of time, wherein an elevation is an indication for initiation of any of IL-1, IL-6, and/or IL-8 inhibitors. The “natural phenomenon” is the correlation between increased interleukin levels, specifically IL-1, IL-6 and/or IL-8, and initiation of an inhibitor of these specific interleukins. The “abstract” idea is comparing the expression of levels of these interleukins at two different points, before and after treatment with an agent that binds to CLEVER-1. Dependent claim 14 further includes measuring interferon-gamma measurements. Dependent claims 2 and 3 further limit the agent that binds to CLEVER-1 expression, and dependent claims 4-7 further limit the interleukin inhibitors. These claims are merely the data gathering steps.
Step 2A(2): Does the claim recite additional elements that integrate the judicial exception into a practical application?
The claims do not meet prong two of step 2A because the combination of additional elements fails to integrate the judicial exception into practical application. The “active step” in claim 13 is “administration of the an agent that is capable of binding to CLEVER-1”. This step occurs before to application of the judicial exception (comparing the expression levels of the interleukins) and is merely a data gathering step. Recited active steps of the claims impose no meaningful limit on the scope of the claims and are recited at a high level of generality such that substantially all methods of measuring any of the interleukin expressions recited would conventionally and routinely perform such steps. Routine data gathering in order to observe a natural phenomenon/ natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/ natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc. The claims also fail to apply or use a judicial exception to affect a particular treatment or prophylaxis for disease or medical condition. The claims also do not effect a transformation or reduction of a particular article to a different state or thing, as discussed in MPEP 2106.05(c).
Step 2B: Does the claim recite an element that amounts to significantly more than the judicial exception?
A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations of measuring gene expressions (“Step 2B”). Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s). The method of measuring the levels of interleukins after treatment with anti-cancer drugs is routine and known in the art. Fousek et al (Fousek et al (Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression. Pharmacol Ther. 2021 Mar;219:107692) teaches that the levels of IL-8 were increased after treatment with certain anti-tumor drugs. [see pg 4, column 5.2] Feng et al. (Serum levels of IL-6, IL-8, and IL-10 are indicators of prognosis in pancreatic cancer. Journal of International Medical Research. 2018;46(12):5228-5236) teaches measuring cytokines, such as IL-6 and IL-8, can be used for prediction of treatment outcome. [see at least pg 5233, first column]
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception when there’s increased, or even decreased, expression of the above genes, and fails to add any elements that amount to significantly more than the judicial exception.
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 2-7, 9, 10, and 12-20 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. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to a method for monitoring a patient’s response to anti—CLEVER-1 therapy and evaluating the need for combination therapy comprising an inhibitor of interleukin and/or respective interleukin receptor, when an agent capable of binding to CLEVER-1 has been administered. The claims recite that the interleukin inhibitors are IL-1 inhibitor or receptor inhibitor, IL-6 inhibitor, or IL-8 inhibitors, or their respective receptor inhibitors.
Dependent claims 2 and 3 recite that the agent capable of inhibiting CELVER1 expression or capable of binding to CLEVER-1 is an antibody, a humanized monoclonal anti-CLEVER1 antibody. Dependent claim 6 recite that the agent capable of binding to interferon alpha/beta receptor (IFNAR).
Dependent claims 4-5 recite that the inhibitors of interleukin or the respective interleukin receptive comprises an antibody or a fragment, peptides, RNA, small molecule, or macromolecule.
Thus, the claims define the agents by the following:
IL-1-, IL-6, IL-8 and IFNAR inhibitors by function only, wherein the function is to bind and inhibit to IL-1, IL-6, IL-8 or their respective receptors.
CLEVER-1 agent: is defined by function only, which is to bind to CLEVER-1 or inhibit the expression. Thus, the claims define the CLEVER-1 agent as any agent that inhibits the function of CLEVER-1, whether that is direct or indirect binding.
The instant specification states the following:
Interleukin inhibitors: The instant specification define the inhibitors of interleukin and/or respective interleukin receptors as antibody, RNA, small molecules. [see 0049-0053 of published spec] The instant specification provides the following examples:
IL-1: Anakinra [0053]
IL-6: Tocilizumab, Siltuximab [0054]
Il-8: Reparixin and Navarixin [0055]
IFNAR: The instant specification defines the agent that is capable of binding to IFNAR as any type of type 1 interferon binding agonists, which may be antibodies, peptides, or molecule thereof. The instant specification provides examples of Rebif, Avonex, Traumakine.
Anti-CLEVER 1 agent: The instant specification defines one example of anti-CLEVER-1 antibody, bexmarilimab.
With regards to any agent that binds to the targets above, it is well established in the art that predicting any protein function from any sequence and structure is a difficult problem. Whisstock et al. (Quarterly Reviews in Biophysics. 36(3):307-340, 2003) teaches that although many families of proteins contain homologues with the same function, homologous proteins often have different functions as the sequences progressively diverge [pg 309] Whisstock teaches that assigning a function to an amino acid sequence based upon similarity becomes significantly more complex as the similarity between the sequence and a putative homologue falls. Whisstock teaches that while it is hopeful that similar proteins will share similar functions, substitution of a single, critically placed amino acid in an active-site may be sufficient to alter a protein’s role fundamentally [pg 321-323] Bowie et al (Deciphering the message in protein sequences: tolerance to amino acid substitutions. Science. 1990 Mar 16;247(4948):1306-10) teaches that an amino acid sequence encodes a message that determines the shape and function of a protein and that it is the ability of these proteins to fold into unique 3-D structures that allows them to function and carry out the instructions of the genome. Bowie et al further teaches that the problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinations to ascertain functional aspects of the protein is extremely complex [pg 1306] Bowie et al. further teaches that while it is known that many amino acid substitutions are possible in any given protein, the position within the protein's sequence where such amino acid substitutions can be made with a reasonable expectation of maintaining function are limited. Certain positions in the sequence are critical to the 3-D structure/function relationship and these regions can tolerate only conservative substitutions or no substitutions at all [page 1306] Burgess et al. (Possible dissociation of the heparin-binding and mitogenic activities of heparin-binding (acidic fibroblast) growth factor-1 from its receptor-binding activities by site-directed mutagenesis of a single lysine residue. J Cell Biol. 1990;111(5 Pt 1):2129-2138) and Lazar et al (Transforming growth factor alpha: mutation of aspartic acid 47 and leucine 48 results in different biological activities. Mol Cell Biol. 1988 Mar;8(3):1247-52) both teach that even a single amino acid substitution will often dramatically affect the biological activity and characteristics of a protein. Briukhovetska et al (Interleukins in cancer: from biology to therapy. Nat Rev Cancer 21, 481–499; 2021) teaches targeting interleukins for treatments of cancers, and teaches the limited number of known inhibitors in the art. However, Briukhovetska teaches that treatment by interleukins is challenging due to effectiveness and serious adverse drug reactions,
With regards to the antibodies specifically, it was well established in the art that the formation of an intact antigen-binding site in an antibody usually required the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three “complementarity determining regions” (“CDRs”) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro & Fransson, Frontiers in Bioscience 2008; 13:1619-33; (see Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1). Humanized antibodies comprise only the CDRs, or in some cases an abbreviated subset of residues within the CDRs, of a parental rodent antibody in the context of human framework sequences. Id. at Section 4. All of the CDRs of the heavy and light chain, in their proper order of CDR1, then 2, then 3, and in the context of framework sequences which maintain their required conformation are generally required to produce a humanized antibody in which the heavy and light chains associate to form an antigen-binding region that binds the same antigen as the parental rodent antibody. Id. at Section 4.
Antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (Gershoni et al., Epitope Mapping, Biodrugs 2007; 21 (3): 145-156 page 146 section 1.1). The skilled artisan therefore understood that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence and length of VH-CDR3.
To provide adequate written description and evidence of possession of the claimed agents, the instant specification can structurally describe representative polypeptides, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.).
Although Applicants may argue that it is possible to screen for proteins that function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The CLEVER-1, IL-1, IL-6, and IL-8 antigens provides no information about the structure of any protein or polypeptide that inhibits it.
Given the lack of representative examples to support the full scope of the claimed products, as demonstrated in the specification and prior art, and lack of reasonable structure-function correlation with regards to the unknown sequences, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of any of the components that function as claimed.
Claims 2-7, 9, 10, and 12-20 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The enablement rejection is directed towards whether increased interleukin IL-1, IL-6, and/or IL-8 levels is indicative of a need for treatment with IL-1, IL-6, and/or IL-8 inhibitors.
The claims are drawn to a method for monitoring a patient’s response to anti—CLEVER-1 therapy and evaluating the need for combination therapy comprising an inhibitor of interleukin and/or respective interleukin receptor, when an agent capable of binding to CLEVER-1 has been administered, the method comprising: (1) obtaining a sample from the patient at a first point in time prior to the administration of the agent capable of binding to CLEVER-1 to a patient, (2) obtaining a sample from the patient at a later point in time after the administration of an agent capable of binding to CLEVER-1 to a patient; (3) measuring a level of interleukin IL-1, IL-6 and/or IL-8 from the obtained samples, (4) comparing the level of IL-1, IL-6 and/or IL-8 measured from the sample obtained at a later point of time to the expression level of IL-1, IL-6 and/or IL-8 measured from the sample obtained at a first point of time, wherein an elevation in interleukin IL-1, IL-6 and/or IL-8 levels is an indication for initiation the concomitant administration of IL-1 inhibitor and/or an inhibitor of the respective receptor, IL-6 inhibitor and/or an inhibitor of the respective receptor, IL-8 inhibitor and/or an inhibitor of the respective receptor, or any combination of thereof. Thus, the claims recite that an increase in the interleukins after treatment with an anti-CLEVER-1 agent results in administration of the inhibitor of the respective interleukin in any disease state.
The instant specification recites that the present invention may be useful for treating disease states with an exhausted immune response, which are not responsive to anti-CLEVER-1 agent or interleukin inhibitors. The instant specification recites that that this can be used in disease states such as cancer, infectious disease, chronic infection, influenza or corona infection. [pg 16 and 17 of the instant specification. The instant specification recites a study wherein serum samples are taken prior to initiating an anti-CLEVER-1 antibody, and then 7 days after beginning therapy. The instant specification recites that in clinical trial NCT03733990 there has been an increase in serum interferon gamma levels, as well as IL-6 and IL-8, in cancer patients.
It is well known in the art that interleukins are signaling molecules that are cortical in regulating several immune responses and can be increased during times of infection or inflammation. Al-Qahtani et al (Pro-Inflammatory and Anti-Inflammatory Interleukins in Infectious Diseases: A Comprehensive Review. Trop Med Infect Dis. 2024;9(1):13. Published 2024 Jan 4) teaches that proinflammatory interleukins, such as IL-1 and IL-6 are important for initiating immune responses and that they also influence the development of memory T-cells which are essential for long-term immunity and that the balance of proinflammatory and anti-inflammatory interleukins is crucial. Briukhovetska et al (Interleukins in cancer: from biology to therapy. Nat Rev Cancer 21, 481–499; 2021) teaches targeting interleukins for treatments of diseases such as cancer, and teaches the limited number of known inhibitors in the art. Briukhovetska teaches that treatment by interleukins is challenging due to effectiveness and serious adverse drug reactions. Thus, given that there could be a reason why there are increased levels of interleukin, such as times of inflammation and infection, and given the challenges of administering interleukin inhibitors, the method is not enabling for administering an interleukin inhibitor due to elevations in IL-1, IL-6 and/or IL-8.
MPEP 2164.01 recites that “The test of enablement is not whether any experimentation is necessary, but whether, if experimentation is necessary, it is undue. In re Angstadt, 537 F.2d 498, 504, 190 USPQ 214, 219 (CCPA 1976)”. The experimentation needed to practice this method is undue and unreasonable as it requires determining which situation which be indicative of administering an interleukin inhibitor after increased levels of IL-6, IL-8, and/or IL-1, and this experimentation is not routine in the art. A person skilled in the art will not be able to use the invention without undue experimentation. (In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)) Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
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 3, 12, 18, and 19 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.
Claim 3 recites the limitation "…the humanized monoclonal anti-CLEVER-1 antibody.” Claim 3 depends on claim 2, claim 2 recites “an antibody or a fragment thereof” but does not recite the specific type of antibody.
Claim 12 recites “The method according to claim 3, wherein the bexmarilimab…” Claim 3 does not recite “bexmarilimab.”
There is insufficient antecedent basis for these limitations in the claims.
Conclusion
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/SARAH A ALSOMAIRY/Examiner, Art Unit 1646
/Zachariah Lucas/Supervisory Patent Examiner, Art Unit 1600