DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Priority
The instant application, filed 07/11/2023, is a 371 filing of PCT/CN2022/071674, filed 01/12/2022, and claims foreign priority to CN20211003278.5, filed 01/12/2021.
Status of Claims/Application
Applicant’s preliminary amendment of 07/11/2023 is acknowledged. Claims 4, 6-7, 9-13, 17-20, and 26 are amended; claims 3, 5, 15-16, 21-25, and 27-39 are cancelled; and claims 41-42 are new.
Claims 1-2, 4, 6-14, 17-20, 26, and 40-42 are currently pending and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/11/2023 and 12/05/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements have been considered by the examiner.
Claim Rejections - 35 USC § 112(a)
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.
Scope of Enablement
Claims 18-20, 26, 41, and 42 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 alleviating, ameliorating or inhibiting a disease or condition, does not reasonably provide enablement for preventing a disease or condition. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
Enablement is considered in view of the Wands factors (MPEP 2164.01(a)). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue,’ not 'experimentation.'" (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all of these factors are considered, a sufficient amount for a prima facie case are discussed below.
The nature of the invention
Claim 18 recites a method of treating a disease or condition comprising administering to a patient in need thereof the antibody or antigen binding fragment thereof of claim 1 to eliminate, inhibit, or reduce CD5 activity, thereby preventing, alleviating, ameliorating, or inhibiting the disease or condition. Claim 19 further limits the disease or condition to being cancer or autoimmune diseases, and claims 20 and 26 further limit the type of cancer.
Claim 41 recites a method of treating a disease or condition comprising administering to a patient in need thereof the fusion protein of claim 7 to eliminate, inhibit, or reduce CD5 activity, thereby preventing, alleviating, ameliorating or inhibiting the disease or condition. Claim 42 further limits the disease or condition to being cancer or an autoimmune disease.
The breadth of the claims
The claims are broad in that they encompass preventing a disease or condition using the antibodies or fragments thereof of claim 1 or the fusion protein of claim 7.
The specification does not define “preventing” or “prevention”. In absence of a limiting definition by the applicants, “prevention” is interpreted as defined according to IIME as provided in Wojtczak, A. (2002) Glossary of Medical Education Terms Medical Teacher 24(4): 357; 1-25. IIME defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (page 16, “Prevention”). IIME states that “primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe.” IIME states that “secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health”. IIME further states that tertiary prevention consists of the measures available to reduce or eliminate long-term impairments and disabilities, minimize suffering caused by existing departures from good health”.
Thus, in its broadest reasonable interpretation, the prevention of a disease or condition suggests that that the onset of the condition never occurs and the patient’s health is protected and preserved.
The amount or direction provided by the inventor / the existence of working examples
The examples of the instant disclosure detail the enrichment of antibody clones targeting CD5 protein from phage antibody library by affinity panning (Example 1, page 14), the screening of clones from the enriched phage pools by ELISA and FACS (Example 2, page 16), and the identification of monoclonal specificity by FACs using multiple cell lines (Example 3, page 19). The examples further evaluated antibody specificity by ELISA using antigens from different companies (Example 4, page 21), measured the affinity of anti-CD5 single domain antibodies (Example 5, page 22), and studied binding of tandem single domain antibodies to CD5+ targets (Example 6, page 24).
While the examples do demonstrate that the single domain antibodies, and fusion proteins thereof, are able to specifically bind CD5, the examples do not demonstrate prevention of any disease or condition using the antibodies or fusion proteins.
Additionally, the disclosure does not identify, or demonstrate through working examples, a method that can be used by one of ordinary skill in the art to predictably identify a patient that would predictably develop a disease or condition, including cancer or an autoimmune disease, in order to establish that the disease or condition was prevented through administration of the antibody or fusion protein and the elimination, inhibition or reduction of CD5 activity.
The state of the prior art / the level of predictability in the art
There are also no art recognized methods that could be used to predictably determine that a condition or disease, such as cancer or an autoimmune disease, onset was prevented using the claimed method, or to identify patients who would have predictably developed a disease or condition in order to establish that prevention was achieved using the claimed therapeutic approach. The state of the art indicates CD5 activity is involved in immune regulation and is associated with a wide range of diseases and conditions demonstrating the breadth of the scope covered by instant claim 18. The art also demonstrates that prevention of diseases, such as cancer and autoimmune disorders, was not predictable.
Dong, J., et al (2025) The multiple functions of CD5 in disease related to immune disorders Annals of Medicine 57(1); 2519682; 1-12 teaches that CD5 is a critical regulator of the immune system and a transmembrane glycoprotein expressed on T cells and the surface of certain B cells. Over the years, numerous studies have demonstrated that CD5 is involved in the regulation of immune responses, maintenance of immune tolerance and modulation of cell survival and apoptosis. Beyond these functions, CD5 also plays a role in immunotherapy, recognition of pathogen-associated molecular patterns, regulation of inflammatory processes, prediction of poor tumor prognosis, and clearance of macromolecules. Immune aberrant disorders – such as infections, chronic inflammation, malignancies, and autoimmune diseases- arise when the immune system becomes dysregulated (abstract). The capacity of CD5 to mediate both activation and suppression within the immune system renders it a paradoxical entity- simultaneously functioning as a defender against pathogenic insult and a potential contributor to immune-mediated tissue damage. Dong provides a review exploring the involvement of CD5 in pathogenesis of four major immune-related disease categories including infections, inflammatory conditions, tumors, and autoimmune disorders and dissects the underlying signaling mechanisms of CD5 in these pathological contexts (page 2, left column, last paragraph). Dong concludes that advances in CD5 targeted immunotherapy have focused on membrane epitopes, with promising developments. Despite these advances, further studies are needed to elucidate the molecular mechanisms regulating CD5 expression across various biological processes and to establish whether CD5 can serve as a viable immunotherapeutic target in broader contexts (paragraph bridging pages 7-8).
Lewandowska, A.M., et al (2017) Environmental risk factors for cancer – review paper Ann. Agric. Environ. Med. 26(1); 1-7 teaches that the cancerous process is a result of disturbed cell function. This is due to the accumulation of many genetic and epigenetic changes within the cell, expressed in the accumulation of chromosomal or molecular aberrations, which leads to genetic instability. It is difficult to assess the validity of individual etiological factors, but it can be concluded that interaction of various risk factors has the largest contribution for the development of cancer. Environmental, exogenous and endogenous factors, as well as individual factors, including genetic predisposition, contribute to the development of cancer (page 1, right column, paragraph 1). Lewandowska discusses numerous factors that contribute to the development of cancer including physical factors such as exposure to electromagnetic fields, ionizing radiation, and ultraviolet radiation (pages 2-3); chemical factors including tobacco smoking, alcohol, and other chemicals (pages 3-4); and biological factors including diet, physical activity, mutagenic and carcinogenic compounds in food, nitrosoamines, and infections (pages 4-5). Lewandowska teaches that, additionally, some epidemiological research suggests that the influence of environmental factors will further affect the cell’s genetic material. This is connected with the spreading of carcinogens in various geographical zones. While some are well known and can be modified, there are certain factors that cannot be fully controlled, such as industrialization (page 6, left column, paragraph 2).
The teachings of Lewandowska demonstrate that, while it was known that cancer is caused by disturbed cell function, numerous factors had been identified that could lead to such disfunction and cell disfunction is likely caused by the interaction of various risk factors. Lewandowska also teaches factors such as genetic predisposition and environmental factors that can contribute to the formation of cancer but are beyond the control of an individual subject. These teachings demonstrate that there was no specific known cause of cancer and, therefore, suggest that there would be no method to predictably determine that cancer would have developed in order to establish that it was prevented.
DeCensi, A., et al (2015) Barriers to preventative therapy for breast and other major cancers and strategies to improve uptake ecancer 9(595); 1-12 teaches that the global cancer burden continues to rise but the utilization of preventative therapy has been poor due to various barriers. DeCensi teaches barriers such as the lack of physician and patient awareness, fear of side effects, and licensing and indemnity issues. DeCensi provides a review discussing the barriers and proposes strategies to overcome them including improving awareness and countering prejudices by highlighting the important differences between preventative therapy and cancer treatment. DeCensi further teaches that future research to improve therapeutic cancer prevention needs to include improvements in the prediction of benefits and harms and improvements in safety profiles of existing agents by experimentation with dose (abstract). DeCensi teaches that for preventative therapy, we cannot identify individuals whose cancer was prevented or risk was substantially reduced because of the lack of measurable biomarkers of efficacy that currently exist for other diseases such as cardiovascular diseases, prevention of diabetes complications or osteoporotic bone fractures. Therefore, from that person’s point of view, they either took medication unnecessarily or, in the worst-case scenario, unnecessarily suffered the adverse effects of such therapy (page 2, paragraph 1).
The teachings of DeCensi demonstrate that, while preventative therapies could be beneficial if various barriers are overcome, there was no method known that could be used to identify individuals whose cancer was prevented because of the lack of measurable biomarkers.
Rosenblum, M.D., et al (2015) Mechanisms of human autoimmunity J Clin Invest 125(6); 2228-2233 teaches that autoimmune diseases are a significant clinical problem. Current therapies have shown great promise in many of these diseases. However, most of the current therapeutic agents target the terminal phase of inflammation and do not address the fundamental problems that are responsible for the initiation and progression of the autoimmune process. Tackling these diseases at their source will require understanding of how the abnormal immune reactions arise, how they are sustained and the intrinsic mechanisms used to suppress these responses in healthy individuals (page 2228, left column, paragraph 1). Rosenblum teaches that because most patients with autoimmune disease develop symptoms well after the abnormal immune reaction begins, it is often difficult to pinpoint the factors responsible for the initiation of disease. Although animal models are informative, there are in fact few models of spontaneous autoimmunity that reliably mimic the human disorders (page 2228, paragraph bridging columns). Autoimmune diseases, like many other complex disorders, are believed to arise from a combination of genetic and environmental factors (page 2228, right column, paragraph 1). Rosenblum teaches factors that are thought to cause autoimmune related diseases including genetic predisposition, such as HLA alleles, cytokine and cytokine receptor genetic polymorphisms, and polymorphisms of multiple genes involved in human immune functioning; environmental triggers, such as infection, microbiome, and traumatic triggers; and defective regulation of the immune system (page 2230, Figure 2). Rosenblum teaches that understanding and successfully treating human autoimmune disease continues to be a significant challenge but incredible progress has been made. Although we have yet to be able to successfully prevent the match from being lit, we are making serious headway in dampening the flames and, in some cases, extinguish the fire (page 2232, paragraph bridging columns).
The teachings of Rosenblum establish that, while progress has been made, the cause of autoimmune diseases is still not well understood. As such, Rosenblum demonstrates that there is no known method that could be used to identify that a patient would predictably develop an autoimmune disease in order to establish that the disease was prevented using the claimed method.
The quantity of experimentation needed to make or use the invention based on the content of the disclosure
As discussed above, there is no disclosed or art recognized method through which an ordinarily skilled artisan would be able to determine that a patient would have predictably developed a disease or condition, including cancer or an autoimmune disease, in order to utilize the claimed treatment as a preventative measure. Furthermore, there is no known or disclosed method that could be used to establish that the disease or condition was prevented as there is no predictable way to know that the subject being treated would have developed a disease or condition without the treatment. As such, in order to implement the invention as claimed, one of ordinary skill in the art would have to participate in undue experimentation to identify a method that could be used to establish that a disease or condition was prevented, with the possibility that no such method could be found.
In view of the Wands factors discussed above, a person of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the claimed invention. As such, the instant claims were determined to not meet the scope of enablement requirement of 35 USC 112(a).
Written Description
Claims 1-2, 4, 6-8, 11-14, 17-20, 26, and 40-42 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.
Claim 1 recites a CD5 targeting antibody or antigen binding fragment thereof, wherein the antibody comprises a heavy chain variable region with HCDRs 1-3 selected from groups (1) – (4). The claim further recites “or the antibody comprises a variant of the combination of CDR sequences in any of (1)-(4), wherein compared to the CDR sequences in any one of (1)-(4), the variant has at least 90% sequence identity, or comprise a total of at least 1 and no more than 10, or nor more than 5, 4, 3, 2, or 1, amino acid changes in the CDR sequences.” As such, claim 1 is drawn to a genus of antibodies or antigen binding fragments that can comprise as little as 90% sequence identity to the claimed CDRs or as many as 10 amino acid changes in the CDR sequences, all of which are claimed as having the function of targeting CD5.
Claim 7 recites a fusion protein comprising one or two antigen binding functional moieties, wherein each of the antigen-binding functional moieties comprises the antibody or antigen binding fragment thereof of claim 1. Claim 8 recites that the two antigen-binding moieties respectively bind to the same or different antigenic epitopes. Claims 7 and 8 are drawn to the genus of antibodies recited in claim 1 and claim 8 further limits the antigen-binding moieties to having the function of binding to the same or different antigenic epitopes.
Claims 18-20, 26, and 41-42 further recite functions that the antibodies/antigen binding fragments of fusion proteins thereof, must perform including the treatment of a disease or condition.
Claim 2 depends on claim 1 and recites that the amino acid sequence of the heavy chain variable region is selected from any one of (1)-(4), which recites amino acid sequences “or a heavy chain variable region having at least 90% identity therewith.” As such, the claim remains drawn to the genus of claim 1 which encompasses heavy chain antibodies with as little as 90% sequence identity in the CDRs. The claim encompasses the function of being a CD5-targeting antibody. Additionally, the claim recites “an amino acid sequence” as set forth in the SEQ ID NOs recited in each of (1)-(4). In the broadest reasonable interpretation of “an amino acid sequence”, the claim encompasses even portions of the recited sequences, including those as small as a couple of amino acids.
Claim 14 depends on claim 13 and ultimately on claim 1 and recites that the nucleic acid molecule that encodes the antibody or antigen binding fragment thereof comprises “a nucleotide sequence” as set forth in any one of SEQ ID NOs: 13-16. In the broadest reasonable interpretation of “a nucleotide sequence”, the claim encompasses even portions of the recited sequences, including those as small as a few nucleotides.
The instant claims are drawn to a genus of CD5-targeting antibodies all of which are claimed as having the recited functions as discussed in detail above. The instant disclosure, however, does not demonstrate a representative number of species of the claimed genus performing the claimed functions. The disclosure also does not provide a structure-function correlation that could be used to predictably identify which species of the claimed genus would be capable of performing the claimed functions, particularly in the absence of a full complement of CDRs (three for single domain antibodies), which are the art recognized binding sites of antibodies.
The examples of the instant disclosure detail the enrichment of antibody clones targeting CD5 protein from phage antibody library by affinity panning (Example 1, page 14), the screening of clones from the enriched phage pools by ELISA and FACS (Example 2, page 16), and the identification of monoclonal specificity by FACs using multiple cell lines (Example 3, page 19). The examples further evaluated antibody specificity by ELISA using antigens from different companies (Example 4, page 21), measured the affinity of anti-CD5 single domain antibodies (Example 5, page 22), and studied binding of tandem single domain antibodies to CD5+ targets (Example 6, page 24). Of the antibodies identified in the specification, clone ID #s 42, 60, 61, and 62 represent the species of the instantly claimed invention that applicant was in possession of at the effective filing date of the claimed invention. Page 22 of the instant specification provides the following table identifying the CDRs of the antibody clones:
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These antibodies, with the full complement of 3 CDRs with 100% identity in the CDRs, represents the single domain antibodies that applicant was in possession of at the time of the effective filing date.
Furthermore, it is not apparent that the instant specification provides any information regarding which antigenic epitopes are bound by the species of single domain antibodies that were characterized. The instant specification defines “epitope” as referring to the portion of a molecule that is bound by an antigen binding protein (page 12), and states that single domain antibodies have gained attention, in part, because of their easy combination with other target or epitope antibodies (page 15). The specification, however, does not provide a structure-function correlation that could be used to establish that the antigenic epitopes of the two antigen-binding functional moieties are the same or different.
The prior art also does not provide a representative number of species of the claimed genus nor does the prior art provide a structure function correlation that can be used to predictably identify which species of the claimed genus would perform the claimed functions. Rather, the state of the art suggests that antibody structure-function is not predictable, particularly in the absence of a full complement of CDRs.
Bathula, N.V., et al (2021) Nanobodies: The future of antibody-based immune therapeutics Cancer biotherapy and radiopharmaceuticals 36; 109-122 teaches that crystallography studies revealed many dynamic features of VHH domain antibodies, such as it is composed of four framework regions (FR) with nine β-sheets separated by loops, which include three hypervariable regions, or CDRs (page 110, right column). The CDR1, located towards the N-terminal region, has high variability, but nonetheless contributes to the binding strength of the domain in collaboration with CDR2, particularly by formation of an interloop disulfide bond with CDR3. The CDR3 is mainly engaged in antigen recognition and is longer than in the conventional VH domain. The longer CD3 gives increased flexibility for antigen binding and specificity variations. Furthermore, in many nanobodies, CDR3 domains have protruding ends, which improves their ability to reach and interact with the epitopes located in protein crevices and enzyme-active domains. All of these properties contribute to the convex surface of VHH, which supplements its ability to interact with the antigen cavities (page 111, left column, paragraph 3).
Hoey, R.J., et al (2019) Structure and development of single domain antibodies as modules for therapeutics and diagnostics Experimental biology and medicine 244; 1568-1576 teaches that VHH domains typically rely heavily on CDR3 for interactions with antigens. Notably, an elongated CDR3 loop provides VHH significant versatility in its ability to interact with target molecules. Unlike conventional antibodies, VHH domains have been observed to interact with antigens in protruding/extended conformations, which allow the antibody to bind protein clefts/pockets, including enzyme active sites. In addition, the CDR3 loop can produce a structurally flat paratope using CDR1/3, CDR1/2/3, and CDR2/3/FW, with some possessing more convex or concave paratopes (paragraph bridging columns, page 1569).
The teachings of Bathula and Hoey demonstrate that antigen binding specificity and strength of single domain antibodies depends on the full complement 3 CDRs all of which, together, form the paratope of the binding domain.
Rojas, G. (2022) Understanding and Modulating Antibody Fine Specificity: Lessons from Combinatorial Biology Antibodies 11(48); 1-22, which was published approximately a year after the effective filing date of the claimed invention, demonstrates that antibody structure and function were still not predictable even after the effective filing date. For instance, Rojas teaches that epitope mapping results using mutagenesis scanning challenge our notions of conservative and nonconservative amino acid replacements. Several measures have been proposed to evaluate the difference between amino acids, based on physico-chemical distance between them, mutational distance, or evolutionary exchangeability. Tolerability profile to mutations within functional epitopes does not adjust strictly to any of these rules. The critical attributes of each amino acid that should be kept to maintain recognition depend on the particular antibody. For instance, sometimes only tyrosine and phenylalanine residues can be exchanged without effecting antigenicity, pointing to the relevance of their almost-identical aromatic rings, whereas in other epitopes, tyrosine and histidine are exchangeable, reflecting that two different rings can fulfill a similar functional role (page 11, paragraph 1).
Teachings which demonstrate that, even years after the effective filing date of the claimed invention, modifications, even those using conservative substitutions, were not predictable.
With regards to epitope binding, the art demonstrates that the structure-function relationship between antibody structure and the epitope it binds to was not predictable.
For instance, Hummer, A.M., et al (2022) Advances in computational structure-based antibody design Current Opinion in Structural Biology 74(102379); 1-7, herein “Hummer”, teaches that traditional methods for antibody development, such as deriving antibodies from hybridomas of inoculated animals or from library assembly followed by display techniques are not only costly and time consuming but also are not necessarily able to produce antibodies that bind to the desired site (epitope) on an antigen. Hummer teaches that computational antibody design methods offer a way to overcome these limitations, but are held back by the lack of accurate antibody and antigen structures (page 1, right column, paragraph 2). Hummer provides a review on how advances in protein structure prediction and other areas are bringing us closer to being able to entirely computationally designed antibodies that bind strongly to a defined epitope (page 1, right column, paragraph 3) demonstrating that in 2022 predictable structure function relationships were still not known. Hummer acknowledges this in their discussion of future directions stating that “Several challenges still remain for true computational structure-based antibody design. While there has been great progress in protein structure prediction, current methods are not yet able to accurately predict the position of the side chain atoms or structural changes on binding. For antibodies, accurately modeling the CDR-H3 loop remains a major obstacle. Additionally, improvements in paratope and epitope prediction, both in terms of accuracy and specificity (predicting the types of binding interactions for residues), will be needed to help improve docking for high-throughput virtual screening.” (page 4, right column, paragraph 3).
Hummer teaches the difficulties in predicting the relationship between antibody structure and the epitopes to which they bind demonstrating a lack of predictability in the field between antibody structure and function.
It is not evident from the disclosure, or the prior art, that applicant was in possession of a representative number of species supporting the entire scope of the claimed genus of CD5-targeting antibodies that are encompassed by the instant the claims. Additionally, there is no disclosed or art recognized structure-function relationship between antibody structure and functionality which would allow for the predictable modification of the claimed sequences while maintaining the claimed functions. There is also no species or art disclosed methods that would allow for the prediction of the antigenic epitopes bound by species within the claimed genus Therefore, the instant claims were found to not meet the written description requirement.
It is noted that there would be support for variation in the framework regions if the full complement of 3 CDRs were limited to 100% identity.
Claims 6 and 12 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.
Claim 6 depends on claim 1 and recites “wherein the binding KD value of the antibody to the CD5 antigen measured by biolayer interferometry is lower than 10-7 M.”
Claim 12 depends on claim 7 and recites “wherein the EC50 value of the binding between the fusion protein and CD5 positive cells determined by flow cytometry is 1-5 nm.”
As discussed in the written description section above regarding claims 1 and 7, the claims are drawn to a genus of CD5 targeting antibodies or fragments thereof.
The instant claims contain functional language by claiming the antibody or fusion protein by what it does rather than by what it is. See MPEP 2173.05(g). In the case of the instant claim, the antibody is claimed based on the equilibrium dissociation constant (KD) with which it binds and not the structure of the antibody which would result in said KD or the EC50 between the binding of a fusion protein and CD5 positive cells, rather than the structure of the fusion protein that would result in such EC50 values. It is noted that, while claims 6 and 12 ultimately depend on claim 1, which does provide some structure, the claims remain drawn to a genus of CD5 targeting antibodies claimed by a function for which there is not sufficient structure claimed or described structure-function correlation.
The instant disclosure identifies KD as the equilibrium dissociation constant between an antibody and its antigen, that is, the ratio of koff/kon. The KD value can be used to measure the binding affinity between an antibody and its antigen. The disclosure further identifies EC50 as being the concentration that causes 50% of the maximal effect. When used in flow cytometry to indicate the binding ability of antibody molecules to corresponding antigens or cells expressing antigens, it can refer to the concentration of antibody molecules that produces half of the maximal detection signal.
The instant disclosure, however, does not support the full scope of the claimed genus with an adequate number of species.
The examples of the instant disclosure detail the production and characterization of anti-CD5 single domain antibodies referenced as clones #42, 60, 61, and 62 (pages 21-22, Example 5). The examples further tested the affinity between the CD5 sdAbs and the antigen in Example 5, and provides KD (M) results for each antibody in table 2 on page 24. As reported, clones #42, 60, 61, and 62 have a binding KD that is lower than 107. These antibodies represent the species of claim 6 that applicant was in possession of at the time of the effective filing date.
The examples further studied the affinity between a fusion protein of 61-42-rFc and CD5 positive cells in Example 6 (page 24), and provides the results for four different cell lines in Table 3. As shown, the average apparent affinity (nM) ranges from 0.64-4.02, depending on the cell line tested. The example concludes that the CD5 tandem single-domain antibody rabbit Fc furoin protein 61-42-rFc has EC50 values all in the range of 1-5 nM. The fusion protein studied, 61-42-rFc, represents the species of claim 12 that applicant was in possession of at the time of the effective filing date.
The disclosure also does not provide a structure-function relationship which would allow an ordinarily skilled artisan to recognize which antibody structures within the claimed genus would function with the claimed KD or EC50 values.
The prior art also does not provide a representative number of species as to support the claimed genus, nor does the art provide a structure-function correlation that would allow for the predictable identification of which antibodies or fusion proteins within the claimed genus would have the claimed function. Rather, the prior art suggests that binding affinity (KD) and EC50 are dependent on the structure of the proteins.
For instance, Hoey, which is discussed above, further teaches that, with growing interest in the use of single domain antibodies for antibody applications, new methods to generate or enhance the VHH scaffold have emerged. Despite the single domain architecture, VHH domains have been amendable to CDR grafting, where the binding affinity/specificity from one VHH is transferred to another VHH framework through substituting the CDR loop residues (page 1571, right column, paragraph 2). A common objective after initial generation of an antibody targeting an antibody of interest includes affinity maturation, whereby one or more protein engineering strategies are used to increase the antibody’s affinity for the antigen, often resulting in the improvement of binding constants by 10-fold or more. Typically, antibody maturation of antibodies involves modifying the gene sequences encoding the residues of the CDR loops to introduce or optimize interactions, e.g., hydrogen bonds, salt bridges, van der Waals, with the antigen. Generation of mutant sequences can be accomplished through scanning and screening individual residues one at a time or through varying multiple residues simultaneously through combinatorial libraries and in vitro display methods. Hoey teaches that experimental techniques are complemented through structural and computational methods to aid in affinity maturation processes (page 1572, left column, paragraph 1). Hoey further teaches that evidence has been provided that the VHH framework and antigen interface both contribute to affinity and are suitable for affinity maturation (page 1572, left column, paragraph 2).
The reference Hummer, also discussed above, further teaches that “It will also be essential to have suitable metrics for evaluating designed antibodies. Tools for predicting antibody-antigen binding affinity could fill such a role, however both machine learning and physics-based methods currently struggle to achieve the required levels of accuracy… advances in binding affinity prediction would enable discrimination between designed antibodies based on binding strength. As such, constructs carried forward for experimentation and further development could be rationally selected.” (paragraph bridging pages 4 and 5).
Rabia, L.A., et al (2018) Understanding an overcoming trade-offs between antibody affinity, specificity, stability and solubility Biochem Eng J. 137; 365-374 teaches that, most antibodies identified during the initial discovery process are not suitable for therapeutic use and require additional optimization. For example, the binding affinities are not high enough for therapeutic applications and must be enhanced through in vitro antibody display methods. However, these methods have an increased risk of producing antibodies with poor biophysical properties. An outstanding challenge in the field is that optimizing properties, such as affinity, can lead to defects in other properties, such as stability, specificity, and solubility. The resulting trade-offs between improvements in some properties and reductions in others highlight that they are often interdependent and cannot be easily separated (page 2, paragraph 3). The importance of affinity/stability trade-offs have been highlighted for single-domain (VH) antibodies, where investigators introduced mutations throughout the VH framework and CDRs using error-prone PCR and displayed the libraries on the surface of yeast. The libraries were sorted to identify antibody variants with high affinity binding and expression. After a single round of mutagenesis and selection, an antibody variant was identified with three mutations that displayed increased affinity, but significantly reduced stability. Further studies revealed the strongly destabilizing effects of the affinity-enhancing mutations (page 3, paragraph 2). Rabia also teaches that mutations that increase affinity – such as those that simply increase hydrophobicity or charge – also reduce specificity (page 4, paragraph 3). Rabia teaches that there are several important areas of future research that are key to minimizing trade-offs between different antibody properties during discovery and development of antibody therapeutics. First, it will be important to develop methods for predicting antibody specificity based on antibody sequence and structure. Some of the key factors that determine antibody specificity are becoming clearer, including the numbers of charged, hydrophobic and hydrophilic residues in the CDRs, as well as the net charge of the variable regions. However, methods are needed to collectively describe these disparate findings and provide guidelines for identifying antibody variants with high specificity based only on their amino acid sequences or their combined sequences and structures. (paragraph bridging pages 8-9).
Based on these teachings, Hoey, Hummer, and Rabia all teach difficulties in predicting the relationship between antibody structure and the affinity with which they bind their desired antigen and the potency of the antibody/fusion proteins thereof. The art also suggests that the binding affinity, or KD values, and, therefore EC50 values, depends on the whole antibody structure and was not/is not predictable.
It is not evident by the disclosure or the prior art, that applicant was in possession of a representative number of species of antibodies wherein the binding KD value of the antibody to the CD5 antigen measured by biolayer interferometry is lower than 10-7 M; or wherein the EC50 value of the binding between the fusion protein and CD5 positive cells determined by flow cytometry is 1-5 nm as claimed. Furthermore, as discussed above, there is no disclosed or art recognized correlation between structure and function which would allow for the predictable identification of antibodies/fusion proteins that bind to CD5 with the claimed KD/EC50 values.
Therefore, the instant claim was determined not to meet the written description requirement of 35 USC 112(a).
Double Patenting
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 conflicting claims 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); 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 nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) 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 www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
18/261,067
Claims 1, 4, 6-9, 12-13, 17-20, 26, and 40-42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6-7, 10, 16, 23, 26, 28, 30-32, 34, and 36-41 of copending Application No. 18/261,067 in view of US 2020/0276326 A1 (Boitano, A., et al) 03 Sept 2020.
App’067 claims chimeric antigen receptors (CARs), comprising a CD5 binding domain, wherein the CD5 binding domain comprises one or more antibodies or fragments thereof specifically binding to CD5, wherein the antibody comprises a HCDR1, HCDR2, and HCDR3 selected from the recited combinations. The CDRs claimed in App’067 are the same as those recited in the instant claims. App’067 further claims that the CD5 binding domain comprises at least two antibodies that bind CD5, that the antibody is a single-domain antibody, and that the binding domain comprises a plurality of single domain antibodies linked by linker fragments. App’067 further claims an isolated nucleic acid encoding the CAR and a vector comprising the nucleic acid molecule. App’067 claims a pharmaceutical composition comprising an immune cell expressing the CAR as well as methods of using the immune effector cells to treat a disease or condition associated with CD5, including a cancer or malignant tumor. App’067 further claims that the disease or condition is a T lymphoblastic lymphoma or mantle cell lymphoma.
The difference between the claims of App’067 and the instantly claimed invention is that the instantly claimed invention is directed towards the CD5 binding domains and does not include their use in CARs. The use of the CD5 binding domain(s) on their own, not included in CARs, however, would have been obvious in view of the prior art.
For instance, US’326 teaches anti-CD5 antibodies and antigen binding fragments thereof for use in treating, for example, a stem cell disorder, cancer, or autoimmune disease, among other hematological and proliferative diseases. Compositions and methods for depleting populations of CD5+ cells, such as CD5+ cancer cells and CD5+ immune cells are also disclosed and can be used to treat cancers and autoimmune diseases directly as stand-alone therapies (abstract; [0006]).
It would have been prima facie obvious to one of ordinary skill in the art to modify the claims of App’067 to include CD5 targeting antibodies, antigen binding fragments, or fusion proteins in addition to the claimed CARs based on the teachings of US’326 which demonstrates that antibodies to CD5 alone can be used to treat cancers and autoimmune diseases. An ordinarily skilled artisan would have reasonably recognized that the CD5 targeting antibody, comprising the same CDR sequences, would bind to CD5 whether they were included in a CAR polypeptide or not, providing a reasonable expectation of success.
Claim 11 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6-7, 10, 16, 23, 26, 28, 30-32, 34, and 36-41 of copending Application No. 18/261,067 in view of US 2020/0276326 A1 (Boitano, A., et al) 03 Sept 2020 as applied to claim 7 above, and in further view of Schutze, K., et al (2018) CD28-specific biparatopic heavy chain antibodies display potent complement dependent cytotoxicity against multiple myeloma cells Frontiers in Immunology 9(2553); 1-11.
The claims of App’067 modified by US’326 render instant claim 7 obvious as discussed in detail above.
While App’067 recites a binding domain comprising a plurality of single domain antibodies linked by linker fragments, App’067 does not claim that the linker fragments are as set forth in instant SEQ ID NO: 21.
Schutze teaches that the variable domain of heavy chain antibodies that naturally occur in camelids is called VHH or nanobody. Nanobodies exhibit several advantages over conventional antibodies. The single domain format greatly facilitates construction of bispecific and biparatopic dimers by genetically linking two nanobodies with a flexible peptide linker (paragraph bridging columns, page 2). Schutze studied CD38 nanobodies and teaches that the combination of two CD38 hcAbs elicited potent CDC when the two hcAbs recognized distinct epitopes. Such constructs sought to exploit the high solubility of nanobodies to construct highly soluble biparatopic nanobody based hcAbs that contain a tandem pair of CD38 specific nanobodies (page 2, right column, paragraph 2).
Schutze teaches that the soluble nature of nanobodies allows for easy reformatting of nanobodies into homo- and heteromeric dimers by linking the C-terminus of one nanobody to the N-terminus of another nanobody by a flexible linker, e.g., (G4S)n (page 5, right column, paragraph 2). Schutze also exemplifies a (G4S)3 linker (page 9, right column, paragraph 1), which is the same as the linker of instant claim 11.
It would have been prima facie obvious to one of ordinary skill in the art to modify the fusion protein taught by the combination of App’067 and US’326 by using the (G4S)3 linker disclosed by Schutze. It would have been obvious to use the linker, and an ordinarily skilled artisan would have had a reasonable expectation of success, as Schutze teaches that the flexible linker can be used to form single domain antibody fusion proteins.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/AUDREY L BUTTICE/Examiner, Art Unit 1647
/SCARLETT Y GOON/Supervisory Patent Examiner
Art Unit 1693