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
Status of the Claims
1. Claims 1-159 are the original claims filed 3/2/2023. In the Preliminary Amendment of 6/14/2023, claims 3-17, 21-22, 136, and 158 are amended and Claims 23-77, 79-135, 137-157, and 159 are cancelled. Claims 1-22, 78, 136 and 158 are all the claims.
Priority
2. USAN 18/177,571, filed 03/02/2023, Claims Priority from Provisional Application 63/316,338, filed 03/03/2022.
Information Disclosure Statement
3. As of 11/12/2025, a total of one (1) IDS is filed: 10/27/2023. The corresponding initialed and dated 1449 form is considered and of record.
Objections
Specification
4. The disclosure is objected to because of the following informalities:
a) The use of the term ATCC, GenBank, Alexa, Octet, PROTAC, TALEN, lucanix, which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
5. The abstract of the disclosure is objected to because of the term “3E10.” The term "3E10" can refer to a specific lupus autoantibody that penetrates cells to inhibit DNA repair, a reovirus sigmaNS protein, or a general structural term for a 3₁₀ helix. The specification defines the meaning of 3E10 as a laboratory definition for a specific murine anti-DNA antibody:
[0006] The murine anti-DNA antibody 3E10 is known to penetrate cells and at least partially localizes to the nucleus of the cell. See, for example, Weisbart R. H. et al. 1998. J. Autoimmun.; 11:539-546, the contents of which is incorporated by reference herein in its entirety. As such, it has been suggested that 3E10 and derivatives thereof may serve as a targeting agent for the delivery of therapeutic agents in vivo.
[0078] As used herein, a “3E10 antibody” refers to an antibody with a set of heavy chain CDRs (VH CDR1, VH CDR2, and VH CDR3), identified according to the Kabat system, comprising amino acid sequences that vary from SEQ ID NOS: 58, 59, and 60 by no more than two amino acids each, respectively, a set of light chain CDRs (VL CDR1, VL CDR2, and VL CRD3) comprising amino acid sequences that vary from SEQ ID NOS: 61, 62, and 63 by no more than two amino acids each, respectively, and that binds nucleic acids. As described herein, the 3E10 antigen is a polynucleotide.
[0102] In some embodiments, a humanized 3E10 antibody or antigen binding fragment thereof binds and/or inhibits Rad51. See, e.g., Turchick, et al., Nucleic Acids Res., 45(20): 11782-11799 (2017), WO 2020/047344, and WO 2020/047353, each of which is specifically incorporated by reference herein, in its entirety.
A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
6. Claims 1-22, 78, 136 and 158 are objected to because of the following informalities:
a) Claims 1-22, 78, 136 and 158 are objected to because of the term “3E10.” The term "3E10" can refer to a specific lupus autoantibody that penetrates cells to inhibit DNA repair, a reovirus sigmaNS protein, a general structural term for a 3₁₀ helix or RAD51. The specification defines the meaning of 3E10 as a laboratory definition for a specific murine anti-DNA antibody:
[0006] The murine anti-DNA antibody 3E10 is known to penetrate cells and at least partially localizes to the nucleus of the cell. See, for example, Weisbart R. H. et al. 1998. J. Autoimmun.; 11:539-546, the contents of which is incorporated by reference herein in its entirety. As such, it has been suggested that 3E10 and derivatives thereof may serve as a targeting agent for the delivery of therapeutic agents in vivo.
[0078] As used herein, a “3E10 antibody” refers to an antibody with a set of heavy chain CDRs (VH CDR1, VH CDR2, and VH CDR3), identified according to the Kabat system, comprising amino acid sequences that vary from SEQ ID NOS: 58, 59, and 60 by no more than two amino acids each, respectively, a set of light chain CDRs (VL CDR1, VL CDR2, and VL CRD3) comprising amino acid sequences that vary from SEQ ID NOS: 61, 62, and 63 by no more than two amino acids each, respectively, and that binds nucleic acids. As described herein, the 3E10 antigen is a polynucleotide.
[0102] In some embodiments, a humanized 3E10 antibody or antigen binding fragment thereof binds and/or inhibits Rad51. See, e.g., Turchick, et al., Nucleic Acids Res., 45(20): 11782-11799 (2017), WO 2020/047344, and WO 2020/047353, each of which is specifically incorporated by reference herein, in its entirety.
Appropriate correction is required.
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.
Written Description
7. Claims 1-17, 78, 136 and 158 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 interpretation
Claims 1-17, 78 and 158 are drawn to humanized 3E10 antibodies and antigen binding fragments thereof.
Claim 136 is drawn to treating a cancer with a humanized 3E10 antibody and antigen binding fragment thereof of claim 1.
As regards claims 1-17, 21, 78, 136 and 158, there is at least 97% identity for the VL/LC regions for the recited sequence(s) and at least 95% identity for the VH/HC regions for the recited sequence(s). AS regards claim 21 that depends from claim 1, additional substitutions are recited of from 1-7 relative to the sets of VHCDR1-3 and VL CDR1-3 recited in the claim.
“% identity”/ “% identical”: the specification teaches insertions, deletions and substitutions are acceptable; variation for an antibody structure may differ by at least amino acid; framework regions can be conservative or different.
[0060] As used herein, the terms “antibody variant” or “variant antibody” refer to an antibody that differs from a parent antibody by virtue of at least one amino acid modification, “IgG variant” or “variant IgG” as used herein is meant an antibody that differs from a parent IgG (again, in many cases, from a human IgG sequence) by virtue of at least one amino acid modification, and “immunoglobulin variant” or “variant immunoglobulin” as used herein is meant an immunoglobulin sequence that differs from that of a parent immunoglobulin sequence by virtue of at least one amino acid modification. “Fc variant” or “variant Fc” as used herein is meant a protein comprising an amino acid modification in an Fc domain as compared to an Fc domain of human IgG1, IgG2, IgG3, or IgG4, as further described herein.
[0265] Also included are fragments of antibodies which have nucleic acid delivery activity. The fragments, whether attached to other sequences or not, include insertions, deletions, substitutions, or other selected modifications of particular regions or specific amino acids residues, provided the activity of the fragment is not significantly altered or impaired compared to the nonmodified antibody or antibody fragment.
[0175] While some of the amino acid substitutions described above are fairly conservative substitutions—e.g., an S to T substitution at position 5 of VL CDR1—other substitutions are to amino acids that have vastly different properties—e.g., an M to L substitution at position 14 of VL CDR1, an H to A substitution at position 15 of VL CDR1, and an E to Q substitution at position 6 of VL CDR2. This suggests, without being bound by theory, that at least these positions within the 3E10 CDR framework are tolerant to other amino acid substitutions.
The interpretation encompasses a genus of antibody variants beyond those taught in the specification much less where the antigen is ambiguous. Because applicant seeks patent protection for all such 3E10 antibodies, this genus must be adequately described. A description adequate to satisfy 35 U.S.C. § 112(a) must clearly allow persons of ordinary skill in the art to recognize that the inventor invented what is claimed (Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc) (citation omitted, alteration in original). The purpose of the written description requirement is to “ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent’s specification” (In re Katz Interactive Call Processing Patent Litig. 639 F.3d 1303, 1319 (Fed. Cir 2011).
Scope of the claimed genus
The percent variation may encompass any number and kind of amino acids that are natural or non-natural or even mimetics. The percent variation may encompass the presence of non-naturally occurring thiol groups, e.g., methionine or cysteine, which is potentially disadvantageous because these amino acids can lead to misfolding or mis-conjugation problems.
Here, all of the claims encompass 3E10 antibodies, and variations to the VH and VL domains, in which the variable domains, including the complementarity determining regions (CDRs) could vary relative to the VLC and VHC and CDRs found in the parental antibody in addition to the VL frameworks and VH frameworks. The encompassed antibodies are allowed to vary relative to the parental antibody at any position. The genus encompassed by the claims is therefore very large and there is substantial variation within the genus.
State of the Relevant Art
By the time the invention was made, it was also well-established in the art that the structure each antibody uses to bind its particular epitope on an antigen is structurally distinct and is formed by a recombination event that results in high variability at the amino acid sequence level, even when the same antigen is bound (Edwards et al., J Mol Biol 334:103-118 (2003) (PTO-892); see also Marchalonis et al., Dev & Comp Immunol. 30:223-247 (2006) (PTO-892), summarized in Abstract and Conclusion.
Methods of preparing antibodies from a variety of species to a protein or peptide of interest were well-established in the art at the time the invention was made. But application of those methods to any given antibody was still a matter of trial-and-error testing, and the skilled person could not automatically predict which residues in the CDRs would be tolerant of mutations, or which amino acid substitutions would maintain antigen binding. Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. For example, it is generally the case that absent the fundamental structure provided for by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, a person of ordinary skill cannot visualize or otherwise predict, what an antibody with a particular set of functional properties would look like structurally.
Moreover, persons of ordinary skill in the art have long since acknowledged that even minor changes in the amino acid sequences of the VH and VL, particularly in the CDRs, may dramatically affect antigen-binding function. Lippow, for example, teaches that a single point mutation in the CDR of a parent antibody led to as much as an eightfold improvement in binding affinity in the resulting mutant (p. 1172, left col., lines 7-8 from end of first full paragraph and Table 1a) (Lippow et al., “Computational design of antibody-affinity improvement beyond in vivo maturation,” Nature Biotechnology, 25(10):1171-1176 (2007) (PTO-892).
Sulea teaches that individual point mutations gave an improvement of one order of magnitude in binding affinity, which in turn, generated a 6-fold enhancement of efficacy at the cellular level (Abstract) (Sulea et al., “Application of Assisted Design of Antibody and Protein Therapeutics (ADAPT) improves efficacy of a Clostridium difficile toxin A single-domain antibody," Scientific Reports, 8(260):1-11 (2018) (PTO-892). Hasegawa et al. reports that a single amino acid substitution in the variable region was sufficient to alter the efficiency of biosynthesis and the variant antibody acquired stronger binding affinity to its antigen than the parent (Hasegawa et al., “Single amino acid substitution in LC-CDR1 induces Russell body phenotype that attenuates cellular protein synthesis through elF2a phosphorylation and thereby downregulates IgG secretion despite operational secretory pathway traffic,” MABS, VOL. 9, NO. 5, pp. 854-873 (2017) (PTO-892)). Altshuler teaches that generally, “CDR mutations should not involve residues that can play structural functions (form parts of the domain ‘internal core’, internal salt bridges, hydrogen bonds, etc.).” “Usually these are conservative residues, and any substitution of these residues causes decrease[s] in affinity” (Altshuler et al., “Generation of Recombinant Antibodies and Means for Increasing Their Affinity,” Biochemistry (Moscow), 75(13):1584-1605 (2010) at p. 1600, col. 1, para. 2, lines 1-5 (PTO-892). Accordingly, a person of ordinary skill in the art would have recognized that it was highly unpredictable that any of the CDRs or FRs could be modified to create an unlimited change in amino acids for both the CDRs and FRs of the claimed antibodies, without increasing, eliminating, or in some way altering antigen binding.
Summary of species disclosed in the specification
Applicant’s specification fully teaches in Example 1 seven humanized versions of the 3E10 variable heavy domain (VH-h1 to VH- h7) and six humanized versions of the 3E10 variable light domain (VL-h1-VL-h6) were constructed. Figures 5-10 provide the amino acid sequences for the humanized VH domains, the mature portion of the full HC incorporating the humanized VH, the full-length heavy chain incorporating the humanized VH, the humanized VL domains, the mature portion of the full LC incorporating the humanized VL, and the full-length heavy chain incorporating the humanized VL, respectively. [00444] Out of the 42 possible humanized 3E10 antibodies that could be created from these humanized VH and VL domains, twenty-two constructs were generated, as outlined in Table 1. In Table 1, the variant number refers to the specific combination of humanized VH and VL. For example, Variant 12 refers to a humanized 3E10 antibody that includes humanized VH-h1 and humanized VL-h2 and Variant 41 refers to a humanized 3E10 antibody that includes humanized VH-h4 and humanized VL-h1.
Are the disclosed species representative of the claimed genus?
It is asserted that the disclosed species are not representative of the claimed genus because the claims encompass any manner and kind of amino acid variation so long as the sequence identity it is at least 97% for the VL/LC and at least 95% for the VH/HC. The genus of all possible 3E10 antibodies encompassed by the claimed variation would be structurally distinct but unpredictable whether the structure/function correlation was met for binding to the ambiguous list of potential antigens as discussed herein above. The disclosed species do not include the known 3E10 antibody in the art. Yet the specification does not identify which CDRs, which combination of fewer than all six CDRs, or which subset of residues in the combination of CDRs is essential for binding. Neither the specification nor the prior art provides guidance as to what structural changes can be made to the parent sequences and still predictably arrive at an antibody that binds to the ambiguous list of potential antigens as discussed herein above. The disclosed species therefore do not represent the claimed genus.
Has Applicant provided a common structure sufficient to visualize the genus?
Applicant has not provided a common structure sufficient to visualize the genus of all possible functional variants. While the disclosure provides the amino acid sequences of the humanized heavy and light chain variable region of clones in Table 1, there is no alignment between these and other 3E10 binders that might show similarities among their linear structures. One of ordinary skill in the art would have understood that clones of Table 1 functioned similarly, but would not have known which residues could have been modified while still maintaining selectivity and affinity in their binding, which could be conservatively changed much less which could not be changed at all.
Even in 2021, antibodies are still not understood well enough to allow researchers to predict with certainty what modifications can be made to a primary antibody sequence such that binding is maintained. “[T]he major test of understanding is whether the changes associated with antibody maturation can be predicted with any reasonable accuracy, and whether there is sufficient information for developing therapeutic antibodies,” Vajda et al., “Progress toward improved understanding of antibody maturation,” Current Opinion in Structural Biology, 67 pp. 226-231 (2021 (PTO 892)) at p. 226, col. 2, lines 20-24.
As recently as 2020, researchers were still speculating as to how to reliably identify further putative binders from antibody sequence data, see, e.g., Marks et al., “How repertoire data are changing antibody science,” J. Biol. Chem. 295(29) 9823-9837 (2020 (PTO 892)), acknowledging that “there is a vast amount of the antibody sequence space that remains unknown,” p. 9831, col. 2, para. 2.
Even assuming, arguendo, the protein sequence of “3E10” was known (e.g., a reovirus sigmaNS protein, a general structural term for a 3₁₀ helix, or RAD51), this would not have translated into knowledge of the genus of antibodies that could possibly engage it. Computational and machine learning approaches for sequence-based prediction of paratope-epitope interactions are accumulating, but “it remains unclear whether antibody-antigen binding is predictable” (Akbar et al., Cell Reports 34, 108856, Mar. 16, 2021 at p. 2, col. 2, para. 2 (PTO 892)). The current state of the art continues to work toward finding an effective and efficient prediction tool for reliably assigning antibody structure based on known target epitopes. See e.g., Lo et al., “Conformational epitope matching and prediction based on protein surface spiral features,” BMC Genomics volume 22, Article number: 116 (2021 (PTO 892)) (disclosing new algorithms that calculate physicochemical properties, such as polarity, charge or the secondary structure of residues within the targeted protein sequences, and then applying quantitative matrix analyses or machine-learning algorithms to predict linear and conformational epitopes).
It is asserted that neither the specification nor the state of art at the time of filing disclosed structural features common to the members of the genus for reliably assigning different antibody structures based on sequence data for two antibody clones, which would support the premise that the inventors possessed the full scope of the claimed invention.
Scope of Enablement
8. Claim 136 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 therapy of cancer, in vivo, in a subject using the V66 clone (SEQ ID NO: 69 (3E10-VH) and 90 (3E10-VL)), does not reasonably provide enablement for prevention of just any cancer using the 3E10 antibody variants of claim 1. 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.
Factors to be considered in determining whether undue experimentation is required, are summarized in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability of the art, the breadth of the claims, the quantity of experimentation which would be required in order to practice the invention as claimed.
Claim interpretation
“treat”: the specification is unequivocal in its disclosure that treatment encompasses both therapeutic and prophylactic outcomes for the method application against any cancer.
[0055] As used herein, the term “treat” refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder. In addition, this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
Disclosure in the Specification
The specification discloses use of the V66 clone (SEQ ID NO: 69 (3E10-VH) and 90 (3E10-VL)) in the treatment of cancers in Examples 6-7 and 9-12. The treatment outcomes demonstrate therapeutic but no prophylactic results.
The scope of the claims must bear a reasonable correlation with the scope of enablement. See In re Fisher, 166 USPQ 19 24 (CCPA 1970). Without such guidance, the amount of, in vitro and in vivo, animal model testing for any given antibody of claim 1, is unpredictable and the experimentation left to those skilled in the art is unnecessarily and improperly extensive and undue. See Amgen, Inc. v. Chugai Pharmaceutical Co. Ltd., 927 F,2d 1200, 18 USPQ 1016 (Fed. Cir. 1991) at 18 USPQ 1026 1027 and Ex parte Forman, 230 USPQ 546 (BPAI 1986).
The claims are not commensurate in scope with the enablement provided in the specification. The specification does not support the broad scope of the claims which encompass the modifications to the VH- and VL-domain because the specification does not disclose the following:
The general tolerance to modification and extent of such tolerance for the VH- and VL-domain;
The specific positions and regions of the VH, VL, LC, HC sequence(s) which can be predictably modified and which regions are critical to binding and therapeutic/ prophylactic outcomes; and
The specification provides insufficient guidance as to which of the essentially infinite possible choices of VH- and VL-domain is likely to be successful.
Thus, applicants have not provided sufficient guidance to enable one of ordinary skill in the art to use the claimed VH- and VL-domains in a manner reasonably correlated with the scope of the claims broadly including any number of additions, deletions, and/or substitutions for the genus of antibodies in Claim 1 and from which the method claim depends.
Prior Art Status: Translation of Therapeutics from In vitro to In vivo is Unpredictable
A tumor is a 3-dimensional complex consisting of interacting malignant and non-malignant cells. Vascularisation, perfusion and drug access to the tumor cells are not evenly distributed and this is an important source of heterogeneity in tumor response to drugs. Therefore, prediction of drug effects in an animal subject based solely on in vitro cell based assays or limited in vivo assays is not reliable and further evaluation in animal tumor systems is essential.
Further, inasmuch as in vivo animal drug testing may be a platform technology in a determination of enablement, the complexity and difficulty of drug delivery for cancer treatment is underscored by Voskoglou-Nomikos (Clin. Can. Res. 9:4227-4239 (2003)). Voskoglou-Nomikos conducted a study using the Medline and Cancerlit databases as source material in comparing the clinical predictive value of three pre-clinical laboratory cancer models: the in vitro human cell line (Figure 1); the mouse allograft model; and the human xenograft model (Figures 2 and 3). Significantly when each of the cancer models was analyzed against Phase II activity, there was a negative correlation for the in vitro human cell line models being predictive of good clinical value. No significant correlations between preclinical and clinical activity were observed for any of the relationships examined for the murine allograft model. And the human xenograft model showed good tumor-specific predictive value for NSCLC and ovarian cancers when panels of xenografts were used, but failed to predict clinical performance for breast and colon cancers. Voskoglou-Nomikos suggests that “the existing cancer models and parameters of activity in both the preclinical and clinical settings may have to be redesigned to fit the mode of action of novel cytostatic, antimetastatic, antiangiogenisis or immune-response modulating agents” and “New endpoints of preclinical activity are contemplated such as the demonstration that a new molecule truly hits the intended molecular target” (p.4237, Col. 1, ¶6).
Dennis (Nature 442:739-741 (2006)) also recognizes that human cancer xenograft mouse models for testing new drugs has been and will remain the industry standard or model of choice, but it is not without problems because “many more [drugs] that show positive results in mice have little or no effect in humans” (p. 740, Col. 1, ¶3). Dennis describes transgenic animal mouse models as an alternative to xenograft modeling and the general differences between mice and humans when it comes to tumor modeling: 1) cancers tend to form in different types of tissue, 2) tumors have fewer chromosomal abnormalities, 3) ends of chromosomes (telomeres) are longer, 4) telomere repairing enzyme active in cells, 5) short lifespan, 6) fewer cell divisions (1011) during life than humans (1016), 7) metabolic rate seven time higher than humans, and 8) lab mice are highly inbred and genetically similar.
Cespdes et al. (Clin. Transl. Oncol. 8(5):318-329 (2006)) review the some of the examples of art-recognized animal disease model correlates for the corresponding human disease in Tables 1-3. Cespedes emphasizes the challenges in using animal models as predictive correlates for human responsiveness to therapeutics and sets forth on pp. 318-319 a list of criteria that would represent the ideal in vivo model for studying cancer therapeutics. As regards the use of xenograft modeling, Cespedes teaches:
"One limitation of the xenograft models is precisely their use of an immunocompromised host, which eliminates the possibility of studying the role of the immune system in tumor progression. Some authors also think that cancer and host cells being from different species may limit the occurrence of critical tumor-stroma interactions, leading to an inefficient signaling. The organ of implantation could also become a limitation to the system. Thus, as it has already been described, subcutaneous xenografts infrequently metastasize and are unable to predict response to drugs” (p. 325, Col. 1, ¶2).
In another thorough and detailed review of animal model testing from 2007, Talmadge et al. (Am. J. Pathol 170(3):793-804 (2007)) teach “Indeed primary human tumor xenografts can be predictive of clinical cytotoxic therapy for a given tumor histiotype provided that clinically relevant pharmacological dosing parameters are used. It is noted that human tumor cell lines in contrast to human primary tumor cells have generally been cultured for years losing much of their heterogeneity. This has resulted in undifferentiated tumors lacking the histology and cellular architecture characteristic of the modeled human tumor” (p. 795, Col. 2, ¶2)... and “xenograft tumor models can effectively predict responsive tumor histiotypes; however these models need to incorporate a pharmacological and toxicological foundation to be successful. In addition, animal models can be used to resolve a specific experimental question that can be appropriately translated into clinical trials" (p. 800, Col. 1, ¶2). “In addition to a quantitative determination of anti-tumor activity, responsive preclinical tumor models cane also be used to assess preliminary ADME (adsorption, distribution, metabolism and excretion) information and toxicity" (p. 800, Col, 2, ¶1). Talmadge states that “Before clinical testing, a new drug or drug formulation should demonstrate safety and/or efficacy profile compared with current therapeutics in animal models. The comparison should incorporate rigorous animal models and not be based on highly responsive models, such as ones with rapid outcome that are convenient or with which the investigator is familiar. Furthermore, tumor and animal models should meet specific biological criteria including heterogeneity, appropriate histology, metastatic propensity, and appropriate genetic criteria depending on the targeted drug metabolism, limited immunogenicity, and potential etiology. Last, the model should have the potential to provide a correlation between therapeutic model outcome and clinical activity, optimally with previous documentation of relevance between mice and humans” (p. 800, Col. 2, ¶3).
One skilled in the art would reasonably conclude that evidence obtained in any in vitro assay would not even necessarily correlate with results expected in any animal model. To the extent the claims encompass an intended in vivo treatment effect of any subject, and the specification does not provide sufficient guidance using the genus of antibodies in a method in vivo to treat/prevent any cancer, the POSA could reasonably conclude that Applicants were not in possession of the full scope of the invention at the time of filing.
Prior Art Status: Immunotherapeutics especially cancer therapy is unpredictable
The use of antibody immunotherapy for the treatment of tumors has been shown to have limitations and recognizing the complexity of antibody delivery to tumors in vivo.
Fujimori teaches for further understanding of Mab distribution in the tumor, one must consider as well the microscopic pharmacology: transport across the capillary wall, transport in tumor interstitium, cellular binding and metabolism. Fujimori discusses predictive models for accessing tumor antigen availability by Mab to examine the relationship between affinity and distribution. Fujimori teaches on p. 1196, Col. 2, ¶1:
“One strategy to overcome the binding-site barrier would be to increase the initial Mab dose. Even though Mab concentration in tumor does not always increase linearly as initial Mab concentration increases, a high initial plasma concentration leads to better percolation and results in more uniform distribution in tumor. Increasing Mab dose, however, decreases the specificity ratio and may cause toxicity or other side effects. For each Mab species and set of circumstances, there is an inherent balance of factors. Other causes of heterogeneous distribution include the functional and anatomical heterogeneity of tumors and their vessels..., and the elevated interstitial tissues…”
Beckman teaches on p. 175, Col. 2, ¶2-4:
“Optimizing biodistribution properties of Ab constructs depends on a large number of host and tumor variables. These include: the density and distribution of target Ag in tumors and normal tissues: the degree of target occupancy and residence tiemr equired for tumor cell kill; possible toxicities from normal tissue distribution; tumor size and vascularity; tumor interstitial pressure, convection and diffusion; and metabolism and internilzation rates for Ab-Ag constructs.
An equally large number of Ab construct and therapy variables are available for optimization, including size, charge, and valence; constant region type and glycosylation pattern; presence or absence of a radioisotope or a toxic moiety; dose, route, and schedule of administration; and use of a traditional or a pretargeting strategy. Given the complexity of the problem, systematic preclinical programs may enhance the likelihood of success in subsequent clinical studies. Such preclinical investigations should integrate both experimental and theoretical approaches.
Preclinical studies of a putative Ab-based therapeutic agent can encompass a variety of constructs, differing in molecular weight, affinity, valence, and/or other features of interest, which bind to the same epitope as demonstrated by competition experiments. The Ag density and target affinities should be known for both tumor cells and cross-reacting normal tissues, and the percent target occupancy and required residence time for tumor cell kill should ideally be investigated in vitro. Similarly, rate constants for Ab-Ag internalization should be determined, if applicable. Dose and schedule should be varied and antitumor efficacy, pharmacokinetics, overall biodistribution, homogeneity of intratumoral distribution, and tumor microvessel density and distribution ideally should be measured in tumor-bearing animals with a variety of tumor sizes.”
Studies in tumor-bearing rodents are often confounded by lack of normal tissue reactivity with Ab constructs directed toward human Ags, but studies in transgenic animal can be performed in some instances to alleviate this issue.”
Thurber teaches on p. 1431, Col 2, ¶3:
“Analyzing the fundamental rates that determine antibody uptake and distribution provides a theoretical framework for understanding and interpreting targeting experiments and improving on the limitations of uptake. It also provides a background for a more rational design of in vitro experiments, animal studies, and clinical trials. The insight gained from this type of modeling has multiple implications for imaging and therapy. For example, not all cells are exposed to the “average” concentration obtained in a tumor. A significant portion of cells can survive even if the tumor-averaged concentration is well above the LD50 in vitro. Also, the concentration that cells in a solid tumor are exposed to ([Ab]surf) is well below the plasma concentration. This means that the bulk antibody concentration in an in vitro spheroid experiment is not analogous to the plasma concentration but is actually well below it; large doses are required to overcome this poor extravasation. Knowing the rate of uptake in a tumor and clearance from the plasma and normal tissues also provides estimates of ratios between tumor and normal tissue concentrations, and these ratios are important in both imaging and therapy. These examples illustrate the utility of combining theoretical analysis also suggest ways to rationally improve uptake, and determining the limiting rates is the first step in overcoming these problems.”
Rudnick teaches on p. 155, Col. 2:
“Not strictly limited to tumor cells, target antigen is commonly expressed on normal tissue, found in circulation, and shed into the tumor interstitial space. These nontarget pools of antigens can reduce treatment effectiveness, increase systemic clearance, and increase side-effects (especially for radioimmunoconjugates) by impairing mAb specificity for the tumor.”
and on p. 158, Col. 2, last ¶ - p. 159, Col. 1:
“…antigen selection will be a critical factor for internalization and catabolism of mAbs. The relative rates of antigen recycling and dissociation are important in mAb penetration into tumors. Therefore, in applications dependent on targeting every cell of a tumor, the mAb needs to dissociate before it is internalized and degraded. In the case of ADCC, a slow internalizing antigen would be the best target. However, if one is trying to deliver a cytotoxic agent to the cytoplasm of cells in a limited region of a tumor, such as the vasculature, a mAb with slow dissociation targeting a rapidly recycling antigen would be appropriate. These are just simple examples of the interplay of affinity, avidity, and efficacy in tumor targeting.”
Huang supports and substantiates the challenges for recombinant antibodies as immunotherapeutic agents (p. 403 and 408):
“Genetic engineering has long been employed to increase the affinity of mAb to its target by altering the amino acid sequence in complementary determining region (CDR; Maynard and Georgiou 2000; Reff et al. 2002). However, high specificity must be maintained while increasing antibody affinity as it might augment cross reactivity with other nonspecific antigens, causing unwanted side effects (Hu et al. 2009). High-affinity CDR also can be suboptimal for targeting solid tumors; thus, a suitable affinity may need to be determined (Chames et al. 2009).”
“Many hurdles remain, however, due to the complexity of human immunology as demonstrated by our limited success in chronic infectious diseases and cancer. The approach to combine both active and passive immunotherapies to have synergic effects to maximize desired immune responses may lead a way for treatments of these diseases in the near future.”
Therefore, due to the unpredictability of immune-therapeutics in general and in view of the insufficient guidance and/or working examples concerning the use of the claimed genus of antibodies of claim 1 as immunotherapeutic agents, one skilled in the art could reasonably conclude that the broadly claimed invention was not fully supported for a therapeutic outcome and was not supported for a prophylactic outcome in the specification, and thereby removing applicants from full possession of the invention.
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.
SEQ ID NO
18/177,571
18/841,356
18/841,043
19/150,521
19/167,684
85 VL
85
125
120
85
85
86 VL
86
126
121
86
86
87 VL
87
127
122
87
87
88 VL
88
128
123
88
88
89 VL
89
129
124
89
89
90 VL
90
130
125
90
90
64 VH
64
104
99
64
64
65 VH
65
105
100
65
65
66 VH
66
106
101
66
66
67 VH
67
107
102
67
67
68 VH
68
108
103
68
68
69 VH
69
109
104
69
69
70 VH
70
110
105
70
70
SEQ ID NO
18/177,571
18/841,356
18/841,043
19/150,521
19/167,684
91 LC
91
131
126
91
91
92 LC
92
132
127
92
92
93 LC
93
133
128
93
93
94 LC
94
134
129
94
94
95 LC
95
135
130
95
95
96 LC
96
136
131
96
96
97 LC
97
137
132
97
97
98 LC
98
138
133
98
98
99 LC
99
139
134
99
1045
100 LC
100
140
135
100
100
101 LC
101
141
136
101
101
102 LC
102
142
137
102
102
71 HC
71
111
106
71
71
72 HC
72
112
107
72
72
73 HC
73
113
108
73
73
74 HC
74
114
109
74
74
75 HC
75
115
110
75
(82)
76 HC
76
116
111
76
(83)
77 HC
77
117
112
77
77
78 HC
78
118
113
78
78
79 HC
79
119
114
79
79
80 HC
80
120
115
80
80
81 HC
81
121
116
81
82 HC
82
122
117
82
82
83 HC
83
123
118
83
83
84 HC
84
124
119
84
84
9. Claims 1-22, 78, 136 and 158 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 15, 17, 20, 24, 26, and 59 of copending Application No. 18/841,356 (reference application US 20250170259). The reference is not afforded safe harbor protection under 35 USC 121 because the application does not share continuity nor a restriction/speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because dependent ref claims 20, 24 and 26 recite identical VL, VH, HC and LC sequences (see column 3 in the table above) to those of the instant claimed VL, VH, HC and LC sequences and that in depending from ref claim 1 would necessarily comprise the same VHCDR1-3 and VL CDR1-3.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
10. Claims 1-22, 78, 136 and 158 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 55-56, 80-86 of copending Application No. 18/841,043 (reference application US 20250161484). The reference is not afforded safe harbor protection under 35 USC 121 because the application does not share continuity nor a restriction/speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ref claims recite identical VL, VH, HC and LC sequences (see column 4 in the table above) to those of the instant claimed VL, VH, HC and LC sequences and that in depending from ref claim 1 would necessarily comprise the same VHCDR1-3 and VL CDR1-3.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
11. Claims 1-22, 78, 136 and 158 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 85-89 of copending Application No. 19/150,521 (reference application). The reference is not afforded safe harbor protection under 35 USC 121 because the application does not share continuity nor a restriction/speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ref claims recite identical VL, VH, HC and LC sequences (see column 5 in the table above) to those of the instant claimed VL, VH, HC and LC sequences and that in depending from ref claim 1 would necessarily comprise the same VHCDR1-3 and VL CDR1-3.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
12. Claims 1-22, 78, 136 and 158 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 79-85 of copending Application No. 19/167,684 (reference application). The reference is not afforded safe harbor protection under 35 USC 121 because the application does not share continuity nor a restriction/speciation with the claims of the instant application.
Although the claims at issue are not identical, they are not patentably distinct from each other because the ref claims recite identical VL, VH, HC and LC sequences (see column 6 in the table above) to those of the instant claimed VL, VH, HC and LC sequences and that in depending from ref claim 1 would necessarily comprise the same VHCDR1-3 and VL CDR1-3.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
13. No claims are allowed.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LYNN A. BRISTOL whose telephone number is (571)272-6883. The examiner can normally be reached Mon-Fri 9 AM-5 PM.
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LYNN ANNE BRISTOL
Primary Examiner
Art Unit 1643
/LYNN A BRISTOL/Primary Examiner, Art Unit 1643