Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-9, 13, and 15) in the reply filed on 12/10/2025 is acknowledged. The traversal is on the ground(s) that the subject matter of Group I is sufficiently related that a thorough search for the subject matter of any one Group would encompass a search for the subject matter of the remaining Group. Thus, applicants contend that a search and examination of the entire application could be made without serious burden. Regarding the species election, applicants provisionally elect AB2 from Claim 1 and “proliferative disease” from claim 15. Applicants also elected the species requirement with traverse on the ground that the generic claims are not so broad as to place an unde burden on the Patent Office to search and examine the full scope of the claims.
Upon review and reconsideration, applicant’s arguments are deemed persuasive. The restriction requirement and species requirement mailed 11/13/2025 is withdrawn.
Claims 1-13 and 15 are pending and under consideration.
Specification
The disclosure is objected to because of the following informalities: The specification filed 03/26/2024 is objected on page 47, line 4 for recitation of a amino acid sequence in the absence of a sequence identifier. See 37 CFR 1.821(c). 37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825.
The specification is further objected to for reciting “depth” on page 35, line 28 as this makes the sentence appear grammatically unclear.
Drawings
Similar to paragraph 5 above, Figures 5A-5D are objected to for reciting amino acid sequences in the absence of a sequence identifier.
Claim Objections
Claim 9 is objected to for reciting “F’ab’)2” as it’s not clear what this structure comprises. Is applicant referring to F(ab’)2 which are divalent antibody fragments? Clarification is requested.
Claim 7 is objected to for reciting “comprising comprises” as this phrasing is grammatically unclear.
Claim Rejections - 35 USC § 112
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.
Claim 15 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
First, claim 15 has improper Markush language for reciting “selected in the group” which is unclear. See MPEP 2117. Secondly, the claims are confusing because of the word “including” as it’s not clear if sepsis is its own condition/disease (sepsis per se; see specification page 36, line 1) or if the claim is intended to define a distinct patient population such as sepsis associated with bacterial infections or sepsis-associated viral infection.
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 1-5, 8-13, and 15 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 broadly drawn to antagonist antibodies or antigen binding fragments thereof, defined by a partial structure, that bind to both human and macaque LILRB1 and/or LILRB2. Claim 1-1, designated AB1 defines the antibody by its CDRs: wherein the heavy chain variable domain comprises an H-CDR1 of SEQ ID NO:1, an H-CDR2 of SEQ ID NO:2, and an H-CDR3 of SEQ ID NO:3. The written description issue here is that the light chain variable domain is written in the alternative “and/or”. Thus, the complete structure is not limited to the 6 claimed CDRs as it appears that the light chain is optional. This issue also appears for the AB2 antagonist antibody. Further, claims 2-5 are also directed to a partial structure, 85% sequence identity to a recited VH or VL sequence with the function of binding and inhibiting LiLRB1 and/or LILRB2. The Written description in this case only sets forth the complete 6 CDRs of AB1 (SEQ ID Nos: 1-3 and 5-7) or AB2 (SEQ ID Nos: 9-11 and 13-15) and therefore is not commensurate in scope to the genus of alternative antibody structures that may or may not contain light chain variable domains.
A description of a genus of may be achieved by means of a recitation of a representative number of species, defined by structure, falling within the scope of the genus. However, the instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of antibodies that bind to both human and macaque LILRB1 and/or LILRB2. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the disclosure of one set of CDRs from the heavy chain is insufficient to describe the large diverse genus of antibodies that are capable of binding to LILRB antigens. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe and enable the genus as broadly claimed.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin.
It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites. Chiu et al. (Antibodies 2019 8(4);55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2). The fact that not just one CDR is essential for antigen binding or maintaining the conformation of the antigen binding site, is underscored by Casset et al. (Biochemical and Biophysical Research Communications, Vol. 307, pg. 198-205,2003) which constructed a peptide mimetic of an anti-CD4 monoclonal antibody binding site by rational design and the peptide was designed with 27 residues formed by residues from 5 CDRs (Abstract). Casset et al. also states that although CDR H3 is at the center of most if not all antigen interactions, clearly other CDRs play an important role in the recognition process (page 199, left col.) and this is demonstrated in this work by using all CDRs except L2 and additionally using a framework residue located just before the H3 (see page 202, left col.). Vajdos et al. (Journal of Molecular Biology, Vol. 320, pg. 415-428, 2002) additionally state that antigen binding is primarily mediated by the CDRs and that the more highly conserved framework segments which connect the CDRs are mainly involved in supporting the CDR loop conformations although in some cases framework residues also contact the antigen (page 416, left col.). Thus, even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function. Thus, the art demonstrates that the antibody structure correlated with its antigen-binding function is six defined CDRs, and the position of each CDR.
Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe and enable the genus as broadly claimed.
Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991) clearly states “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). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of second polypeptides, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required.
Thus, only an antibody claiming the six defined CDRs of AB1 or AB2 - but not the full scope of the claims meets the written description.
Claim 15 is 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 method for treating cancer, does not reasonably provide enablement for treating any and all bacterial or viral infections including sepsis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The focus of the enablement inquiry is whether everything within the scope of the claim(s) is/are enabled, at the time of filing, without requiring undue experimentation to make or use the invention. The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims: With respect to claim breadth, the standard under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, entails the determination of what the claims recite and what the claims mean as a whole. The claims are broadly drawn to a method of treating any proliferative disease, any bacterial infection or any viral infection and sepsis in a human subject.
The specification teaches [0239-0242] that the term “bacterial infection” includes the presence of bacteria in or on a subject that would benefit the subject if its growth is inhibited. Thus, in addition to referring to the presence of bacteria, the term “infection” also refers to unwanted resident flora. Further, the bacterial agent causing a bacterial infection may be a gram-positive bacterial agent such as Staphylococcus spp, Streptococci, Enterococcus spp, Leuconostoc spp, Corynebacterium spp, Bacillus spp, Anaerobic Cocci, Actinomyces spp, Clostridium spp, Nocardia spp, Listeria spp, Mycoplasma spp, Mycobacterium spp. or gram negative such as pathogenic Escherichia coli, Bacillus, Pseudomonas, Helicobacter, Legionella, Neisseria gonorrhoeae, Neisseria meningitidis, Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Chlamydia trachomatis, Yersinia pestis, Plasmodium (including Plasmodium facliparum) and Trypanosoma (including Trypanozoma cruzi).
Regarding viral diseases, the specification teaches [0237-0238] that examples of persistent viral infections include but are not limited to cytomegalovirus (CMV) pneumonia, enteritis, and retinitis; Epstein-Barr virus (EBV) lymphoproliferative disorder; fowlpox/zoster virus (varicella-zoster virus, Caused by VZV); HSV-1 and -2 mucositis; HSV-6 encephalitis; BK-virus hemorrhagic cystitis; viral influenza; pneumonia caused by respiratory multinuclear virus (RSV).
Regarding sepsis, the specification teaches [0244] that it is the leading cause of death in critically ill patients, is defined as an infection-induced syndrome involving two or more of the following features of systemic inflammation: fever or hypothermia, leukocytosis or leukopenia, tachycardia and tchypnea or supranormal minute ventilation. Sepsis encompasses systemic inflammatory response syndrome (SIRS), sepsis per se, severe sepsis, septic shock and multiple organ dysfunction syndrome (MODS).
Regarding “proliferative diseases” the only diseases that are described are cancers [0233-0235].
The state of the prior art and the level of predictability in the art at the time of filing: Kang et al. (Cell Cycle, Volume 15, Issue 1, 2016) teach that there are potential therapeutic approaches targeting LILRBs. The dual roles as immune checkpoint molecules and tumor-sustaining factors and a lack of apparent function in normal development and hematopoiesis suggest that LILRBs are ideal targets for treating cancer. A possible approach would be to use recombinant soluble extracellular domains of these receptors or blocking antibodies to competitively block activity. Certain myeloid leukemia, B lymphoid leukemia, and myeloma cells express LILRB3. Of note, (page 29, 1st column) the observed co-expression of LILRB3 with stem cell marker CD34 and with myeloma marker CD138 suggests a role in cancer development. Indeed, inhibition of LILRB3 expression in human leukemia cell lines blocks cell growth. Antibodies against LILRB3 induce cytotoxicity of LILRB3-expressing cells via complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. LILRB3 thus is a potential target for anti-cancer therapy. Antibody conjugate therapeutics that directly target LILRB-expressing malignant cells are also possible options. Regarding pathogen-related infections, Marffy et al. (Front. Immunol. Vol. 11, 12 May 2020) teach (abstract) that neutrophils have a crucial role in defense against microbes. Immune receptors allow neutrophils to sense their environment, with many receptors functioning to recognize signs of infection and to promote antimicrobial effector functions. However, the neutrophil response must be tightly regulated to prevent excessive inflammation and tissue damage, and regulation is achieved by expression of inhibitory receptors that can raise activation thresholds. Thus, inhibiting these receptors could have deleterious effects. Cleavage of antibodies into non-functional forms is an immune evasion strategy used by a broad spectrum of pathogens to reduce classical pathway opsonization, phagocytosis, and killing. LILRA2 interactions with N-terminally truncated antibodies stimulates neutrophils and induces antimicrobial effector functions. However, this only suggests LILRA2 senses and mounts appropriate antimicrobial immune responses against a specific subset of pathogens (page 5, 1st column). In some cases, LILR directly recognize viral, bacterial, and parasitic pathogens. Dengue virus binds to LILRB1 but these interactions are proposed to contribute to immune evasion. Likewise, the human cytomegalovirus (CMV) derived UL18 protein binds LILRB1 and suppresses immune cell activity (page 5, 2nd column) Thus, it is unclear whether antagonistic antibodies would predictably enable the immune system to effectively clear foreign pathogens.
The amount of direction provided by the inventor and the existence of working examples: The instant specification does not provide sufficient guidance and direction that the claimed method would predictably treat sepsis, any viral disease or disorder, or any bacterial disease or disorder. Applicants have not presented any in-vitro or in-vivo models that could reasonably be extrapolated to the successful treatment of viral or bacterial infections. Further the specification does not present any data that discusses treating cancer. Only the state of the art reasonably suggests that some cancers could be treating by administering the claimed antagonistic antibodies.
This lack of experimental guidance in view of the complexities of treating sepsis, or viral diseases, or bacterial diseases would not permit one of skill in the art to reasonably predict or conclude that the claimed method would successfully treat such diseases or disorders.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004)). The instant specification is not enabling for the invention claimed because one cannot follow the guidance presented therein, or within the art at the time of filing, and perform the method claimed without first making a substantial inventive contribution. See also OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("These references provide no more than hope—and hope that a potentially promising drug will treat a particular cancer is not enough to create a reasonable expectation of success in a highly unpredictable art such as this. Indeed, given a 99.5% failure rate and no efficacy data or any other reliable indicator of success, the only reasonable expectation at the time of the invention was failure, not success.").
Therefore, claim 15 is rejected under 35 U.S.C. 112(a) or pre-AIA U.S.C. 112, first paragraph, for failing to meet the full scope of the enablement requirement.
Claim Objections
Claims 6 and 7 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.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643