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 .
Priority
The instant application is claiming the benefit as a continuation of International Application No. PCT/US22/74785, filing date 08/10/2022, which claims the benefit of the prior-filed United States Provisional Patent Application No. 63/231,694, filing date 08/10/2021.
Status of Application/Claims
The preliminary amendment, filed 02/09/2024, is acknowledged. Claims 2-3, 7-9, 16-27, 29-39, 41, 46-55, 58-59, 61, 63, 65, 67, and 69-84 are canceled. Claims 4-6, 10-12, 14-15, 28, 43-44, 56-57, 60, 62, 64, 66, and 68 are currently amended. Claims 1, 4-6, 10-15, 28, 40, 42-45, 56-57, 60, 62, 64, 66, and 68 are currently pending and are examined on the merits herein.
Information Disclosure Statements
The information disclosure statement (IDS) submitted on 02/09/2024 has been fully considered by the examiner.
Specification
The use of the terms Panorex, Ovarex, Zenapax, GraphPad Prism, ThermoFisher Scientific, Pluronic, Leica Biosystems, Life Technologies, Applied Biosystems, TaqMan, The Jackson Laboratory, and Church and Dwight Co., Inc., which are trade names or marks used in commerce, have been noted in this application. The terms should be in all caps wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
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.
Drawings
The drawings are objected to because of poor resolution in the following figures:
Figure 10 A-I: Headings A-H; and, y-axis numbers for I.
Figure 27-29 A-C: scale numbers and text.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1, 10-11, 15, 28, 40, 60, and 64 are objected to for the following:
The following claims recite the phrase “having at least 80%” which should be corrected to “comprising at least 80%”: claim 1, 2 instances; claim 10, 1 instance; claim 15, 4 instances; claim 28, 4 instances; and, claim 40, 1 instance.
The following claims recite the phrase “having at least 90%” which should be corrected to “comprising at least 90%”: claim 11, 1 instance; and, claim 28, 1 instance.
Claim 4 recites “…wherein the antibody comprises a heavy chain variable region sequence having an amino acid sequence set forth in SEQ ID NO: 3”. The term “having” should be replaced with “comprising.”
Claim 5 recites “…wherein the antibody comprises a light chain variable region sequence having an amino acid sequence set forth in SEQ ID NO: 4”. The term “having” should be replaced with “comprising.”
Claim 13 recites “…antibody is provided that can that specifically bind…” which should be corrected to “…antibody is provided that can specifically bind…”.
Claim 14 recites “…comprising a humanized antibody of claim 13” which should be corrected to “…the humanized antibody of claim 13” to clarify proper antecedent basis.
Claim 57 should include the conjunction “and” between the two steps of “measuring…” and “administering…”.
Claims 44, 56-57, 60, 62, 64, 66, and 68 each recite “…a pharmaceutical composition…of claim 1” which should be corrected to “…the pharmaceutical composition…of claim 1” to clarify proper antecedent basis.
Claim 60 recites the limitation “GSL” which should be corrected to “glycosphingolipid”.
Claim 64 appears to have been amended but lacks a status indicator and is thus objected to. The status of every claim in such listing must be indicated after its claim number by one of the following identifiers in a parenthetical expression: (Original), (Currently Amended), (Canceled), (Withdrawn), (Previously Presented), (New), and (Not Entered). See MPEP 1893.01(a)(4).
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 15, 28, 44, 56-57, 60, 62, 64, 66, and 68 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 15 recites an expression vector comprising “(i) a heavy chain variable region nucleic acid sequence having at least an 80% sequence identity to SEQ ID NO: 3; however, SEQ ID NO: 3 is an amino acid sequence, not a nucleic acid sequence. For further examination, the claims are interpreted to reference heavy chain nucleic acid SEQ ID NO: 1.
Claim 28 recites a selection among three pharmaceutical compositions. The second selection recites (i), (ii), (iii). Because no conjunction is recited, it is unclear if all three components are required or if only one component is required. For further examination, the second option of this claim is interpreted to mean “(i)…(ii)… and (iii)...”. Additionally, the third pharmaceutical composition option recites (a) an antibody comprising-(i) and/or (ii)…and (b) a therapeutically effective amount of at least one inhibitor of glycosphingolipid synthesis.” As the antibody recited in (a) is understood to be an inhibitor of glycosphingolipid synthesis as recited in (b), it is unclear if the antibody alone is sufficient to satisfy the requirements of (a) and (b) or if an additional inhibitor of glycosphingolipid synthesis is required. For further examination (b) is interpreted to require “at least one additional inhibitor.” Further, claim 28 recites that the second pharmaceutical composition comprises “(i) a heavy chain variable region nucleic acid sequence having at least an 80% sequence identity to SEQ ID NO: 3; however, SEQ ID NO: 3 is an amino acid sequence, not a nucleic acid sequence. For further examination, the claims are interpreted to reference heavy chain nucleic acid SEQ ID NO: 1.
Claims 44, 56-57, 60, 62, 64, 66, and 68 each recite “a/the pharmaceutical composition, antibody, expression vector, or peptide of claim 1. There is insufficient antecedent basis for the terms “expression vector” and “peptide” in the claim.
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.
Claims 1, 6, 10-12, 28, 4445, 56-57, 60, 62, 64, 66, and 68 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. THIS IS A WRITTEN DESCRIPTION REJECTION.
Regarding instant claims 1, 6, 10-12, 44, 56-57, 60, 62, 64, 66, and 68: Claim 1 is inclusive of a genus of antibodies that specifically binds to a β-1,4-galactosyl-transferase epitope wherein the heavy chain variable and light chain variable region amino acid sequences only require 80% identity to instant SEQ ID NOs: 3 and 4, respectively. Thus, the claims allow for variability in the CDR sequence structure of the antibody.
Regarding instant claim 28: Claim 28 recites a pharmaceutical composition options comprising amino acid and nucleic acid sequences that encode for heavy chain variable and light chain variable region sequences for a genus of antibody that can specifically bind to a β-1,4-galactosyl-transferase epitope wherein only 80% of instant nucleic acid SEQ ID NOs: 1 and 2 or 80% of amino acid SEQ ID NOs 3 and 4 are required. Thus, the claim allows for variability in the CDR sequence structure of the antibody.
Regarding instant claim 45: Claim 45 recites a method of treating colorectal cancer comprising administering a pharmaceutical composition comprising an antibody comprising nucleic acid sequences encoding heavy chain variable and light chain variable region sequences for a genus of antibody wherein only 80% of instant nucleic acid SEQ ID NOs: 1 and 2 are required. Thus, the claim allows for variability in the CDR sequence structure of the antibody.
The instant disclosure suggests that two antibodies are supported by the disclosure: 1) an antibody comprising a heavy chain variable region and light chain variable region encoded by amino acid SEQ ID NOs: 3 and 4, respectively; and, 2) an antibody comprising a heavy chain variable region and light chain variable region encoded by amino acid SEQ ID NOs: 7 and 9, respectively. However, while the several of the instant disclosure’s drawings and examples are drawn to experiments using “an anti-β-1,4-GalT-V antibody,” it is not clear which antibody structure is associated with the supported antibody functions. The disclosure and claims further provide sequences for heavy chain variable and light chain variable amino acid and nucleic acid SEQ ID NOs: 1-4 and 6-9; wherein, nucleic acid SEQ ID NO: 6 encodes for the heavy chain variable amino acid SEQ ID NO: 7 and nucleic acid SEQ ID NO: 8 encodes for light chain variable amino acid SEQ ID NO: 9; and, wherein nucleic acid SEQ ID NO: 1 encodes for the heavy chain variable amino acid SEQ ID NO: 3 and nucleic acid SEQ ID NO: 2 presumably is intended to encode for light chain variable amino acid SEQ ID NO: 4—however, the examiner notes that a translation of the nucleic acid SEQ ID NO: 2 does not produce amino acid SEQ ID NO: 4 as there is a discrepancy in amino acid at position 9 (see translation in figure below, top). In fact, the sequence listing indicates that nucleic acid SEQ ID NOs: 2 and 8 are identical, and thus both encode for a heavy chain amino acid that is not supported by the disclosure (see alignment in figure below, bottom):
[AltContent: textbox ([img-media_image1.png])]
As the claims recite specific amino acid and nucleic acid sequences, the examiner encourages applicant to verify that the sequences recited in the claims are correct (e.g., claim 15 recites an expression vector comprising nucleic acid SEQ ID NO: 2, which does not encode for amino acid SEQ ID NO: 4).
In summary, the disclosure supports ONE antibody comprising amino acid SEQ ID NOs 3 and 4, which respectively encode for structures of ONE heavy chain and ONE light chain. The specification does not disclose, and the art does not teach, structures for the genus of antibodies with the claimed function as is broadly encompassed in the claims. Claims 6, 10-12, 44, 56-57, 60, 62, 64, 66, and 68 are dependent on claim 1 and do not overcome the issue, and are thus also rejected.
In regards to claims to a product defined by function, without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement.
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (see Paul. Fundamental Immunology, 3rd Edition, 1993, pp. 292-295; herein referred to as Paul). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (p.293, col.1-2, lines 3-8, line 31, and lines 27-30).
The instant specification fails to provide sufficient descriptive information, such as definitive structural features that are common to the genus. That is, the specification provides neither a representative number of antibodies that encompass the genus of antibodies with the claimed function nor does it provide a description of structural features that are common to the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species.
The “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
Because the disclosure fails to describe common attributes or characteristics that adequately identify members of the genus, and because the genus is highly variant, the disclosure of an antibody encoded by heavy and light chain variable SEQ ID NOs: 3 and 4, respectively, is insufficient to describe the genus. Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe the genus as broadly claimed.
Claim 66 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. THIS IS A WRITTEN DESCRIPTION REJECTION.
Claim 66 recites a method of treating a subject suffering from or susceptible to migraines or migraine pain comprising administration to the subject an effective amount of the pharmaceutical composition, antibody, expression vector, or peptide of instant claim 1.
The instant disclosure provides the following experiments in support of a method for treatment of:
Colorectal cancer: Figures 1-6, 8-9, 11, 13-18, and 21-29; and, Examples 1-2, 4-13
VEGF-induced tube formation in endothelial cells (i.e., angiogenesis): Figures 10 and 21-22; and, Examples 7-8 and 11.
Atherosclerosis: Example 3
Type II diabetes: Example 3
In summary, the disclosure only provides support for methods of treatment for colorectal cancer, one type of diabetes (i.e., type II diabetes), atherosclerosis, and angiogenesis.
The state of the prior art is such that a methods of treatment for colorectal cancer, atherosclerosis, metabolic syndrome, obesity, diabetes, macular degeneration, and Alzheimer’s disease are supported by the combination of prior art teachings below, which involve abnormal β-1,4-galactosyltransferase V levels or its lactosylceramide metabolic product:
See Lactosylceramide synthase β-1,4-GalT-V: A novel target for the diagnosis and therapy of human colorectal cancer. Biochemical and Biophysical Research Communications, available online 11/28/2018; 508, p.380-386 below for involvement in colorectal cancer.
See Chatterjee, et al. Management of metabolic syndrome and reduction in body weight in type II diabetic mice by inhibiting glycosphingolipid synthesis. Biochemical and Biophysical Research Communications, publication date: 04-30-2020; 525:2, p.455-461 below for involvement in atherosclerosis, metabolic syndrome, diabetes, and obesity.
See Mondal and Mandal. Role of bioactive sphingolipids in inflammation and eye diseases. Adv. Exp. Med. Biol., 2019, 1161, p.1-23 for involvement in angiogenesis and macular degeneration.
See Chatterjee—WO2006023827A2. Methods for treatment of angiogenesis below for involvement in angiogenesis.
See Yu, et al. The involvement of lactosylceramide in central nervous system inflammation related to neurodegenerative disease. Frontiers in Aging Neuroscience, published 07/19/2019; 13:691230, p.1-12 below for involvement in Alzheimer’s disease.
There are no art recognized methods for administering an inhibitor of LacCer or β-1,4-galactosyltransferase. In fact, in a study evaluating LacCer in serum samples from episodic migraine patients (see Peterlin, et al. Interictal, circulating sphingolipids in women with episodic migraine. Neurology, 2015; 85, p.1214-1223; herein referred to as Peterlin), Peterlin found that “There was no association between any of the LacCer species with migraine (tables 2 and 3)” (p.1217, col.2, para.2).
In summary, the instant disclosure does not provide support for a methods encompassing treatment for migraine or migraine pain, and the prior art supports that there is no association between LacCer and migraine.
The “claims merely recite a description of the problem to be solved while claiming all solutions to it and . . . cover any compound later actually invented and determined to fall within the claim’s functional boundaries— leaving it to the pharmaceutical industry to complete an unfinished invention.” Ariad Pharmaceuticals, Inc. v. EliLilly and Co.,598 F.3d 1336, 1353 (Fed. Cir. 2010).
As there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function and because applicant has not provided support for the method of treatment, one of skill in the art would reasonably conclude that the disclosure fails to provide support for methods of treatment as broadly claimed wherein treatment encompasses treatment of migraine.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 6 is rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Rossi, et al.—US20200181264A1. Bispecific antigen-binding molecule (publication date: 06/11/2020; effective filing date: 08/11/2017; herein referred to as Rossi).
Rossi teaches a pharmaceutical composition comprising an antigen binding molecule, which can be a therapeutic antibody ([307]-[315]; [0145]; wherein embodiments include an antibody comprising a heavy chain variable region (VH) sequence comprising or consisting of SEQ ID NO: 21 and comprising a light chain variable sequence (VL) comprising or consisting of 70% or more of SEQ ID NO: 17 ([0174]-[0175]). Rossi’s SEQ ID NO: 17 shares 97.1% identity with instant SEQ ID NO: 4, which encodes for the instantly claimed light chain variable region (see alignment below). Rossi additionally teaches that the antigen-binding molecule or composition [AltContent: textbox (Instant SEQ ID NO: 4 vs Rossi SEQ ID NO: 17 variable light chain region
[img-media_image2.png])]may be administered simultaneously with another therapeutic agent ([0344]).
Regarding the instant claim 1 limitation “wherein the antibody specifically binds to a β-1,4-galactosyltransferase-V epitope”: A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to distinguish the claimed invention from the prior art. To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim because the prior art comprises the claimed sequence identity of instant SEQ ID NO: 4 (see MPEP 2111.02-II).
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Rossi.
Rossi teaches a pharmaceutical composition comprising an antibody amino acid sequence of SEQ ID NO: 17 that comprises at least 80% amino acid identity to the instantly claimed VL amino acid SEQ ID NO: 4 and that specifically binds β-1,4-galactosyltransferase-V. Rossi additionally teaches expression of polypeptides expressing such antibody chains using nucleic acid expression in vectors ([0180]-[0181]).
[AltContent: textbox (Instant nucleic acid SEQ ID NO: 2 amino acid translation:
DVVMTQTPLTLSVTIGQPASISCKSSQSLLDSDGKTYLNWLLQRPGQSPKRLIYLVSKLGSGVPDRFTGSGSGTDFTLKISRVEAEDLGVYYCWQGTHFPRTFGGGTKLEIKR
Translated amino acid SEQ ID NO: 2 vs. instant amino acid SEQ ID NO: 4 VL:
[img-media_image3.png])]Rossi does not specifically teach an expression vector comprising the VL nucleic acid sequence that is at least 80% identical to instant nucleic acid SEQ ID NO: 2 (instant claim 15). However, a routine translation of the nucleic acid sequence of instant SEQ ID NO: 2 results in an amino acid sequence that is 98.8% identical to instant amino acid SEQ ID NO: 4 which encodes for the instantly claimed VL chain for an antibody that specifically binds β-1,4-Galactosyltransferase V and which is taught by Rossi as applied to claim 1 above. Thus, It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to use a reverse translation (routine to one of ordinary skill in the art) of Rossi’s amino acid SEQ ID NO: 17 to obtain a nucleic acid sequence that could be expressed from an expression vector (also taught by Rossi), in order to arrive at a predictable result of producing a VL chain for an antibody that has at least 80% identity to instant SEQ ID NO: 4.
Claims 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Chatterjee—WO2019236722A1. Inhibitors of glycosphingolipid synthesis and methods of use (publication date: 12/12/2019; effective filing date: 06/05/2018; herein referred to as Chatterjee), and further in view of Harding, et al. The immunogenicity of humanized and fully human antibodies. mAbs, 2010, 2:3, p.256-265 (herein referred to as Harding).
Chatterjee teaches compositions comprising inhibitors of glycosphingolipid synthesis and methods of use thereof for therapeutic treatment of disease (p.20, para.2); wherein, embodiments include an antibody that specifically binds β-1,4-Galactosyltransferase V (BGA) or peptides thereof (p.2, para.2). Chatterjee further defines “specifically binds” as binding an epitope: “…the terms "specific binding" or "specifically binding" when used in reference to the interaction of a protein and an antibody or alternative protein scaffold or peptoid or aptamers, means that the interaction is dependent upon the presence of a particular structure (i.e., the antigenic determinant or epitope) on the protein; in other words the antibody is recognizing and binding to a specific protein structure rather than to proteins in general” (p.11, para.5). Chatterjee further teaches that the antibody is inclusive of all species, including human and humanized antibodies and the antigenic target can be from any species (p.7, para.3).
Chatterjee does not specifically teach the motivation for using a humanized antibody (instant claims 13 and 14).
Harding teaches that immunogenic responses to antibody therapeutics can impact both safety and pharmacokinetic properties which can impact utility and efficacy of the drugs (p.256, col.1, para.1); and, that humanization of murine monoclonal antibodies has vastly improved their in vivo tolerability. Harding teaches that humanization, which is the replacement of mouse constant regions and V framework regions of human sequences, results in a significantly less immunogenic product (abstract).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Chatterjee with the teachings of Harding by modifying the BGA antibody and pharmaceutical composition thereof (taught by Chatterjee) to be a humanized antibody (taught by Harding) to arrive at the instantly claimed invention, in order to receive the expected benefit (taught by Harding) that humanization of therapeutic antibodies reduces immunogenicity and improving tolerability. One of ordinary skill would have a reasonable expectation of success because Chatterjee teaches that the BGA antibody can be humanized.
Claims 6, 28, and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Rossi, as applied to claim 1 above; and, further in view of Chatterjee.
Rossi teaches the pharmaceutical composition comprising an antibody that comprises at least 80% identical to the VL amino acid SEQ ID NO: 4 and that specifically binds β-1,4-galactosyltransferase-V, as applied to claim 1 above. Rossi additionally teaches that the antibody composition can be administered with other therapeutic agents ([0344]).
Chatterjee teaches compositions comprising antibodies that specifically bind β-1,4-Galactosyltransferase V (BGA) or peptides thereof (p.2, para.2) for the purpose of treating disease, as described for claims 13-14 above.
Regarding claim 6: In addition to Rossi, as applied to claim 6 above, Chatterjee also teaches that the antibody composition can comprise additional therapeutic agents, such as anti-atherosclerotic agents (p.34, para.1; instant claim 6). Thus, It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Rossi with the teachings of Chatterjee by modifying the composition to additionally comprise at least one other therapeutic agent, in order to arrive at the instantly claimed invention because both Rossi and Chatterjee teach administration of the claimed antibody in conjunction with additional therapeutic agents.
Regarding claim 28: Rossi does not teach that the additional therapeutic agent is an inhibitor of glycosphingolipid synthesis (instant claim 28).
Chatterjee additionally teaches embodiments comprising administration of the BGA antibody in conjunction with other inhibitors of glycosphingolipid synthesis; and, wherein the pharmaceutical compositions can comprise the following glycosphingolipid synthesis inhibitors: D-PDMP, (1R,2R)-nonanoic acid[2-(2',3'- dihydro-benzo [l, 4] dioxin-6'-yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]- amide-L-tartaric acid salt (Genz-123346), BPD, lipids, ceramides or combinations thereof; and, that in certain embodiments, the D-PDMP, (1R,2R)-nonanoic acid[2-(2',3'-dihydro-benzo [l, 4] dioxin-6'yl)-2-hydroxy-1-pyrrolidin-1-ylmethyl-ethyl]- amide-L-tartaric acid salt (Genz-123346), 5 lipids, ceramides or combinations thereof are encapsulated by a biodegradable polymer (p.2, para.4—p.3, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Rossi with the teachings of Chatterjee by modifying the composition comprising the β-1,4-galactosyltransferase-V antibody comprising at least 80% VL SEQ ID NO: 4 (taught by Rossi) to include at least one inhibitor of glycosphingolipid synthesis (taught by Chatterjee) or an anti-atherosclerotic agent as an additional therapeutic agent (taught by Rossi and Chatterjee) to arrive at the instantly claimed invention, in order to receive the expected benefit (taught by Chatterjee) of inhibiting glycosphingolipid synthesis for treatment of disease. One of ordinary skill would have a reasonable expectation of success because Rossi teaches the instantly claimed VL amino acid sequence and Chatterjee teaches several examples of glycosphingolipid synthesis inhibitors, as well as anti-atherosclerotic agents, that can be administered in conjunction with an antibody that specifically binds β-1,4-galactosyltransferase-V.
Regarding claim 56: Rossi does not teach a method of treating autoimmune disease (instant claim 56).
Chatterjee additionally teaches that the BGA antibody treatment is for skin disease or skin associated disorders which comprise inflammatory skin diseases, burns, scars, wounds, lesions, autoimmune diseases, Verucca vulgaris, fungal infections, bacterial infections, virus infections, rosacea or combinations thereof. The scars can be from an injury or as a result of surgery, including cosmetic surgery.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Rossi with the teachings of Chatterjee by modifying the composition comprising the β-1,4-galactosyltransferase-V antibody comprising at least 80% VL SEQ ID NO: 4 (taught by Rossi) to be used in a method of treating autoimmune disease (taught by Chatterjee) to arrive at the instantly claimed invention, in order to receive the expected benefit (taught by Chatterjee) of using an anti-BGA antibody to bind BGA to inhibit glycosphingolipid synthesis for treatment of autoimmune disease. One of ordinary skill would have a reasonable expectation of success because Rossi teaches the instantly claimed VL amino acid sequence and Chatterjee teaches anti-BGA antibody treatment for glycosphingolipid synthesis inhibition and treatment of autoimmune disease.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Rossi and Chatterjee, as applied to claim 1 above; and further in view of Harding, as applied to claims 13-14 above.
Rossi teaches the pharmaceutical composition comprising an antibody that comprises at least 80% identical to the VL amino acid SEQ ID NO: 4 and that specifically binds β-1,4-galactosyltransferase-V, as applied to claim 1 above.
Chatterjee teaches compositions comprising antibodies that specifically bind β-1,4-Galactosyltransferase V (BGA) or peptides thereof (p.2, para.2) for the purpose of treating disease, as described for claims 13-14 above.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Rossi with the teachings of Chatterjee by modifying the composition comprising the β-1,4-galactosyltransferase-V antibody comprising at least 80% VL SEQ ID NO: 4 (taught by Rossi) to include at least one inhibitor of glycosphingolipid synthesis (taught by Chatterjee) or an anti-atherosclerotic agent as an additional therapeutic agent (taught by Rossi and Chatterjee) to arrive at the instantly claimed invention, in order to receive the expected benefit (taught by Chatterjee) of inhibiting glycosphingolipid synthesis for treatment of disease. One of ordinary skill would have a reasonable expectation of success because Rossi teaches the instantly claimed VL amino acid sequence and Chatterjee teaches several examples of glycosphingolipid synthesis inhibitors, as well as anti-atherosclerotic agents, that can be administered in conjunction with an antibody that specifically binds β-1,4-galactosyltransferase-V.
The combination of Rossi/Chatterjee does not teach that the antibody is humanized (instant claim 12).
The combination of Chatterjee and Harding teaches the benefit of using a humanized β-1,4-GalT-V antibody, as described for claim 13 above.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Rossi/Chatterjee with the teachings of Chatterjee/Harding by using the inhibitory β-1,4-GalT-V antibody comprising the claimed VL and VH sequences in a method of treatment (taught by Rossi/Chatterjee), in order to arrive at the instantly claimed invention because the combination of prior art teachings leads to a predictable result of using an antibody that specifically binds and inhibits β-1,4-GalT-V for the benefit of reducing tumor size; and, to further modify the antibody by using a humanized antibody (taught by Harding) to arrive at the instantly claimed invention, in order to receive the expected benefit (taught by Harding) that humanization of therapeutic antibodies reduces immunogenicity and improving tolerability. One of ordinary skill would have a reasonable expectation of success because Chatterjee teaches that the BGA antibody can be humanized.
Claim 42 is rejected under 35 U.S.C. 103 as being unpatentable over Chatterjee, as applied to claim 13; and further in view of Chatterjee, et al. Lactosylceramide synthase β-1,4-GalT-V: A novel target for the diagnosis and therapy of human colorectal cancer. Biochemical and Biophysical Research Communications, available online 11/28/2018; 508, p.380-386 (herein referred to as Chatterjee-2018).
Chatterjee teaches a method of treatment by administering an antibody that specifically binds to BGA, as applied to claims 1, 6, and 28 above.
Chatterjee does not teach that the method of treatment is for colorectal cancer (CRC; instant claim 42).
Chatterjee-2018 teaches that β-1,4-GalT-V gene/protein expression is specifically increased in human colorectal cancer tumors (abstract). Chatterjee-2018 teaches that increased glycosphingolipid (GSL) levels due to aberrant glycosylation
and metabolism in CRC is known and that β-1,4-GalT-V plays a role in GSL synthesis (p.380, col.1-col.2). Chatterjee-2018 also teaches that suppression via gene ablation of β-1,4-GalT-V diminished tumor growth (p.380, col.2); and, that inhibition of GSL synthesis may be a novel approach for the treatment of the life-threatening CRC disease (abstract).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Chatterjee with the teachings of Chatterjee-2018 by using the inhibitory β-1,4-GalT-V antibody in a method of treatment (taught by Chatterjee) for a method of specifically treating CRC (taught by Chatterjee-2018), in order to arrive at the instantly claimed invention because the combination of prior art teachings leads to a predictable result of using an antibody that specifically binds and inhibits β-1,4-GalT-V for the benefit of reducing tumor size. One of ordinary skill in the art would have a reasonable expectation of success because both Chatterjee and Chatterjee-2018 teach treatment of disease via inhibition of β-1,4-GalT-V using an antibody.
Claim 43 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of Chatterjee and Chatterjee-2018, as applied to claim 42 above; and further in view of Harding, as applied to claims 13-14 above.
The combination of Chatterjee and Chatterjee-2018 teaches a method of treatment for CRC using administration of an inhibitory β-1,4-GalT-V antibody, as applied to claim 42 above.
The combination of Chatterjee/Chatterjee-2018 does not teach that the antibody is humanized (instant claim 43).
The combination of Chatterjee and Harding teaches a humanized β-1,4-GalT-V antibody, as described for claim 13 above.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Chatterjee with the teachings of Chatterjee-2018 and Harding by using the inhibitory β-1,4-GalT-V antibody in a method of treatment (taught by Chatterjee) for a method of specifically treating CRC (taught by Chatterjee-2018), in order to arrive at the instantly claimed invention because the combination of prior art teachings leads to a predictable result of using an antibody that specifically binds and inhibits β-1,4-GalT-V for the benefit of reducing tumor size; and, to further modify the antibody by using a humanized antibody (taught by Harding) to arrive at the instantly claimed invention, in order to receive the expected benefit (taught by Harding) that humanization of therapeutic antibodies reduces immunogenicity and improving tolerability. One of ordinary skill would have a reasonable expectation of success because Chatterjee teaches that the BGA antibody can be humanized; and, because Chatterjee-2018 teaches that the antibody can be used for CRC treatment. One of ordinary skill in the art would have a reasonable expectation of success because both Chatterjee and Chatterjee-2018 teach treatment of disease via inhibition of β-1,4-GalT-V using an antibody.
Claims 44-45, 56-57, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of teachings by Rossi, as applied to claims 1 and 15 above; further in view of Chatterjee; and further in view of Chatterjee-2018, as applied to claim 42 above.
Regarding claim 44: Rossi teaches the expression of the instantly claimed amino acid sequence of at least 80% identity to SEQ ID NO: 4 which encodes the instant VL chain of an antibody that specifically binds β-1,4-GalT-V, as well as expression of the polypeptide via nucleic acid expression via an expression vector, as applied to claim 15 above.
The combination of Rossi/Chatterjee teaches a method of treating disease by administering the pharmaceutical composition comprising an inhibitory β-1,4-GalT-V antibody, as applied to claim 28 above.
The combination of Rossi/Chatterjee does not teach that the method of treatment is for CRC (instant claim 44).
The combination of Chatterjee/Chatterjee-2018 teaches a method of treating CRC via administration of an inhibitory antibody that specifically binds β-1,4-GalT-V, as applied to instant claim 42 above.
Thus, It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Rossi/Chatterjee with the teachings of Chatterjee/Chatterjee-2018 by modifying the method of treatment with an inhibitory β-1,4-GalT-V antibody (as taught by Rossi/Chatterjee) to be used specifically for a method of treating CRC (as taught by Chatterjee/Chatterjee-2018), in order to arrive at the instantly claimed invention because the combination of prior art teachings leads to a predictable beneficial result of treating CRC via administration of the β-1,4-GalT-V antibody. One of ordinary skill would have a reasonable expectation of success because Chatterjee-2018 teaches that β-1,4-GalT-V expression and glycosphingolipid synthesis activity contribute to tumor growth and inhibition of β-1,4-GalT-V diminishes CRC tumor growth.
Regarding claim 45: The combination of Rossi’s teachings teaches that a reverse translation (routine to one of ordinary skill in the art) of Rossi’s amino acid SEQ ID NO: 17 results in a nucleic acid sequence that could be expressed from an expression vector (also taught by Rossi), in order to arrive at a predictable result of producing a VL chain for an antibody that has at least 80% identity to instant SEQ ID NO: 4 which encodes for the instantly claimed antibody that specifically binds β-1,4-GalT-V.
The combination of Rossi/Chatterjee teaches a method of treating disease by administering the pharmaceutical composition comprising an inhibitory β-1,4-GalT-V antibody, as applied to claim 28 above.
The combination of Rossi/Chatterjee does not teach that the method of treatment is for CRC (instant claim 45).
The combination of Chatterjee/Chatterjee-2018 teaches a method of treating CRC via administration of an inhibitory antibody that specifically binds β-1,4-GalT-V, as applied to instant claim 42 above.
Thus, It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Rossi/Chatterjee with the teachings of Chatterjee/Chatterjee-2018 by modifying the method of treatment with an β-1,4-GalT-V antibody expressed via a nucleic acid that encodes for the antibody at least 80% identity (as taught by Rossi) that can be used in a method of treatment for inhibiting β-1,4-GalT-V (taught by Rossi/Chatterjee) to be used specifically for a method of treating CRC (as taught by Chatterjee/Chatterjee-2018), in order to arrive at the instantly claimed invention because the combination of prior art teachings leads to a predictable beneficial result of treating CRC via administration of the β-1,4-GalT-V antibody comprised of at least 80% identity to the instantly claimed antibody of the composition. One of ordinary skill would have a reasonable expectation of success because Chatterjee-2018 teaches that β-1,4-GalT-V expression and glycosphingolipid synthesis activity contribute to CRC tumor growth and inhibition of β-1,4-GalT-V diminishes CRC tumor growth.
Regarding claims 56-57 and 60: The combination of Rossi/Chatterjee/Chatterjee-2018 teaches a method of treatment for CRC via administration of a pharmaceutical composition comprising an inhibitory β-1,4-GalT-V antibody via expression of the antibody via an expression vector, as applied to claims 44-45 above.
The combination of Rossi/Chatterjee does not teach a method of diagnosing and treating, and monitoring progression of CRC by measuring levels of β-1,4-GalT-V and/or GSL in a biological sample (instant claims 57 and 60); or, treatment of a disease associated with abnormal levels of β-1,4-GalT-V/CRC (instant claim 56).
In addition to treatment of CRC Chatterjee-2018 teaches that β-1,4-GalT-V gene/protein expression and GSL levels are increased in CRC (abstract; p.280, col.1). Chatterjee-2018 teaches a study wherein they acquired colorectal tissue samples from de-identified cancer patients and evaluated their immunoreactivity to β-1,4-GalT-V antibodies, and assessed β-1,4-GalT-V mass, mRNA expression, enzymatic activity, and GSL end-product levels (p.380, col.2, para.2). Chatterjee-2018 suggests that β-1,4-GalT-V serves as a diagnostic and therapeutic biomarker for the progression of human CRC as Human CRC tissues were found to exhibit strongly positive immunoreactivity
to a β-1,4-GalT-V antibody and to exhibit increased protein mass, activity (synthesis of
lactosylceramide/GSL), and gene expression of β-1,4-GalT-V (p.382, col.1) (i.e., abnormal levels of β-1,4-GalT-V).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the additional teachings of Chatterjee-2018 with the combined teachings of Rossi/Chatterjee/Chatterjee-2018 by measuring β-1,4-GalT-V and/or GSL/lactosylceramide levels in biological samples (taught by Chatterjee-2018) in order to detect increases in β-1,4-GalT-V and/or GSL monitor the progression of CRC (also taught by Chatterjee-2018) to diagnose and monitor the progression of CRC in patients (also taught by Chatterjee-2018) prior to administration of an inhibitory β-1,4-GalT-V antibody for the treatment of CRC (taught by the combination of Rossi/Chatterjee/Chatterjee-2018), to arrive at the instantly claimed invention because Chatterjee-2018 teaches the benefit that β-1,4-GalT-V serves as a biomarker for CRC diagnosis and progression. One of ordinary skill in the art would have a reasonable expectation of success because Chatterjee-2018 teaches methods for β-1,4-GalT-V and/or GSL detection and measurement.
Claims 56 and 68 are rejected under 35 U.S.C. 103 as being unpatentable over the Rossi, Chatterjee, and Chatterjee-2018 as applied to claims 1, 56-57, and 60 above; and, further in view of Chatterjee, et al. Management of metabolic syndrome and reduction in body weight in type II diabetic mice by inhibiting glycosphingolipid synthesis. Biochemical and Biophysical Research Communications, publication date: 04-30-2020; 525:2, p.455-461 (herein referred to as Campbell); and, as evidenced by Jackson Laboratories. Choosing & maintaining mice for type 2 diabetes and obesity research. JAX Mice & Services-Solutions by Therapeutic Area-Metabolic Diseases. Wayback Machine—available online 02/25/2021, p.1-3 (herein referred to as JAX).
The combination of Rossi/Chatterjee/Chatterjee-2018 teaches a method of treatment for CRC/disease with abnormal levels of β-1,4-GalT-V via administration of a pharmaceutical composition comprising an inhibitory β-1,4-GalT-V antibody via expression of the antibody via an expression vector, as applied to claims 44-45 and 56 above.
The combination of Rossi/Chatterjee/Chatterjee-2018 does not teach a method of treating diabetes or obesity (instant claim 56); or, a method of treating metabolic syndrome (instant claim 68).
Campbell teaches management of metabolic syndrome and reduction in body weight in type II diabetic (T2D) mice by inhibiting GSL synthesis with potential applications in humans (title; abstract). Campbell teaches that metabolic syndrome and obesity are characterized by high levels of blood LDL, glucose and triglycerides, with low levels of HDL; that studies support a role for GSLs in human T2D (p.455, col.1, para.1); and, that increased GSL and LacCer levels improve the predictive value of cardiovascular events and death (p.455, col.2, para.2). Campbell teaches that GSLs are integral components of mammalian cell membranes that are synthesized by the transfer of sugars from a nucleotide-sugar to a sphingolipid; that the transfer of galactose from UDP-Gal to glucosylceramide, catalyzed by a β-1,4-galactosyltransferase, generates LacCer (lactosylceramide); and, that the role of LacCer as a signal-transducing agent modulating the actions of several growth factors and proinflammatory molecules, has become apparent. In addition, Campbell teaches that LacCer has been shown to serve as a mitogenic agent, an inducer of angiogenesis, cell migration, and apoptosis, and reverse transport of cholesterol; and, that treatment of cells or mice with inhibitors of GSL synthesis successfully mitigated growth factor-induced phenotypes and atherosclerosis in multiple disease models (p.455, col.2-p.456, col.1, para.1). Campbell further teaches that inhibition of GSL synthesis ameliorates atherosclerosis and aortic intima-media thickening, body weight and triglycerides while increasing HDL levels in db/db T2D mice (p.456-457). As evidenced by JAX, db/db mice are an obese, T2D mouse model (p.1, para.2 and 5; p.2, para.2). Thus, Campbell teaches treatment of T2D obesity, and metabolic syndrome in subjects.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Rossi/Chatterjee/Chatterjee-2018 with the teachings of Campbell and JAX by modifying the method of treatment of a disease wherein the patient exhibits abnormal levels of β-1,4-GalT-V and/or GSL/LacCer (taught by the combination of Rossi/Chatterjee/Chatterjee-2018) to encompass methods of treating metabolic syndrome, diabetes, and obesity, as well as atherosclerosis (taught by Campbell and JAX), in order to arrive at the instantly claimed invention, in order to receive the benefit of reducing GSL levels to treat metabolic syndrome and/or diabetes and/or obesity and/or atherosclerosis. One of ordinary skill in the art would have a reasonable expectation of success because Chatterjee-2018 teaches treatment of CRC, which is a condition of elevated β-1,4-GalT-V and/or GSL/LacCer; Rossi/Chatterjee teaches inhibition of β-1,4-GalT-V via administration of an inhibitory β-1,4-GalT-V antibody composition; Campbell teaches that metabolic syndrome, diabetes, and obesity are characterized by high levels of blood LDL, glucose and triglycerides, with low levels of HDL and that inhibition of GSL synthesis reduced body weight and triglycerides; and, Campbell teaches that inhibition of GSL synthesis ameliorates atherosclerosis.
Claim 62 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of teachings by Rossi, as applied to claims 1 and 15 above; further in view of Chatterjee; and further in view of Mondal and Mandal. Role of bioactive sphingolipids in inflammation and eye diseases. Adv. Exp. Med. Biol., 2019, 1161, p.1-23 (herein referred to as MM).
Rossi teaches the expression of the instantly claimed amino acid sequence of at least 80% identity to SEQ ID NO: 4 which encodes the instant VL chain of an antibody that specifically binds β-1,4-GalT-V as applied to claim 1 above, as well as expression of the polypeptide via nucleic acid expression via an expression vector, as applied to claim 15 above.
The combination of Rossi/Chatterjee teaches a method of treating disease by administering the pharmaceutical composition comprising an inhibitory β-1,4-GalT-V antibody, as applied to claim 28 above.
The combination of Rossi/Chatterjee does not teach that the method of treatment is for treating a subject suffering from macular degeneration (instant claim 62).
MM teaches the role of sphingolipids in inflammation and eye diseases (title); and, that inflammation is a common underlying factor in a diversity of ocular diseases, ranging from macular degeneration, autoimmune uveitis, glaucoma, diabetic retinopathy and microbial infection (abstract). MM teaches that age-related macular degeneration AMD is associated with several pathological disorders, ranging from inflammation, malfunctioning of autophagy and chronic oxidative stress leading to degeneration of retinal pigment epithelium (RPE) and ultimately photoreceptor death with vision loss; and, that the later stages of AMD are categorized as ‘Dry AMD’ or ‘Wet AMD’, wherein wet AMD exhibits both macular atrophy and choroidal neovascularization (p.10, para.2). MM teaches that various sphingolipid metabolites, such as ceramide (Cer), ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P), and lactosylceramide (LacCer) can contribute to ocular inflammatory diseases through multiple pathways; and, that inflammatory stress by reactive oxygen species leads to LacCer accumulation and S1P secretion and induces proliferation of retinal endothelial cells and eventual formation of new vessels (i.e., angiogenesis; abstract). MM teaches that Cer, S1P, C1P, and LacCer are the major signaling molecules regulating key physiological functions and a variety of pathological processes, mainly related to inflammatory responses or inflammation-associated diseases; that LacCer plays a role as a signaling molecular in inflammation-induced proliferation or angiogenesis; and teaches the biosynthetic enyzmes and pathway (p.3, para.2; p.23, Fig.14.1). MM teaches that LacCer acts as a common precursor of all types of the lactose series of complex glycosphingolipids (GSLs, including the gangliosides and globotriosylceramide); and that LacCer synthase/β-1,4-galactosyltransferase converts GlcCer to LacCer (p.6, 2).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to combine the teachings of Rossi/Chatterjee with the teachings of MM by modifying the method of treatment with an inhibitory β-1,4-GalT-V antibody (as taught by Rossi/Chatterjee) to be used specifically for a method of treating macular degeneration (as taught by MM), in order to arrive at the instantly claimed invention because the combination of prior art teachings leads to a predictable beneficial result of treating macular degeneration via administration of the inhibitory β-1,4-GalT-V antibody. One of ordinary skill would have a reasonable expectation of success because MM teaches the role of LacCer in ocular diseases including dry and wet AMD, and LacCer production is dependent on LacCer synthase/β-1,4-galactosyltransferase glycosphingolipid synthesis activity.
Claim 64 is rejected under 35 U.S.C. 103 as being unpatentable over the combination of teachings by Rossi and Chatterjee as applied to claims 1, 6, 15, 28, and 56 above; in further view of Chatterjee-2018 as applied to claims 42 and 56 above; in further view of MM as applied to claim 62 above; and further in view of Yu, et al. The involvement of lactosylceramide in central nervous system inflammation related to neurodegenerative disease. Frontiers in Aging Neuroscience, published 07/19/2019; 13:691230, p.1-12 (herein referred to as Yu).
The combination of Rossi/Chatterjee teaches the expression of the instantly claimed amino acid sequence of at least 80% identity to SEQ ID NO: 4 which encodes the instant VL chain of an antibody that specifically binds β-1,4-GalT-V as applied to claim 1 above, as well as expression of the polypeptide via nucleic acid expression via an expression vector, as applied to claim 15 above, for use in a method of treating disease by administering the pharmaceutical composition comprising an inhibitory β-1,4-GalT-V antibody, as applied to claims 1, 6, 15, 28, and 56 above.
The combination of Chatterjee/Chatterjee-2018 teaches a method of treating CRC, a condition of abnormally increased β-1,4-GalT-V gene/protein expression and GSL levels, via administration of an inhibitory antibody that specifically binds β-1,4-GalT-V, as applied to instant claim 42 and 56 above.
The combination of Rossi/Chatterjee/MM teaches a method for use of the BGA antibody inhibitor in treatment for macular degeneration. MM further teaches the role of LacCer in neurodegenerative diseases of the eye; that LacCer acts as a common precursor of all types of the lactose series of complex glycosphingolipids (GSLs, including the gangliosides and globotriosylceramide); and that LacCer synthase/β-1,4-galactosyltransferase converts GlcCer to LacCer (p.6, 2).
The combination of Rossi/Chatterjee, Chatterjee/Chatterjee-2018, and Rossi/Chatterjee/MM do not teach that the method of treatment is for treating a subject suffering from Alzheimer’s disease (instant claim 64).
Yu teaches the involvement of LacCer in CNS inflammation and neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) (title; abstract; p.2, col.1, para.3), which are all progressive neurodegenerative diseases characterized by irreversible damage to the structure and function of neurons in the brain resulting in neuronal loss (p.2, col.1, para.3).. Yu teaches that LacCer promotes the accumulation of abnormal proteins, abnormal signaling, and neurotoxicity of gangliosides, which leads to the occurrence and further progression of neurodegenerative diseases (p.2, col.1, para.1). Yu also teaches that LacCer synthase is the key enzyme that synthesizes LacCer. Yu also teaches that cell experiments have shown that gangliosides are significantly increased in the H4APPsw cell model of neurodegeneration, p.6, col.1, para.1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Rossi/Chatterjee/Chatterjee-2018/MM with the teachings of Yu by modifying the method of treatment with an inhibitory β-1,4-GalT-V antibody for a neurodegenerative disease (as taught by Rossi/Chatterjee/Chatterjee-2018/MM) to be used specifically for a method of treating Alzheimer’s disease (as taught by Yu), in order to arrive at the instantly claimed invention because the combination of prior art teachings leads to a predictable beneficial result of treating Alzheimer’s disease via administration of the inhibitory β-1,4-GalT-V antibody. One of ordinary skill would have a reasonable expectation of success because MM teaches the role of LacCer in neurodegenerative disease and that LacCer production is dependent on LacCer synthase/β-1,4-galactosyltransferase glycosphingolipid synthesis activity; and, Yu teaches that there is a relationship between increased gangliosides (i.e., LacCer derivatives) and neurodegenerative CNS disease, and Alzheimer’s disease in particular.
Claims 10-11, 28, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over the combination of Rossi/Chatterjee/Chatterjee-2018/MM as applied to claim 1 above; in further view of Chatterjee-2018; in further view of MM; and, further in view of Chatterjee—WO2006023827A2. Methods for treatment of angiogenesis (herein referred to as Chatterjee-2006).
The combination of Rossi/Chatterjee/Chatterjee-2018/MM teaches the expression of the instantly claimed amino acid sequence of at least 80% identity to SEQ ID NO: 4 which encodes the instant VL chain of an antibody that specifically binds β-1,4-GalT-V as applied to claim 1 above, as well as expression of the polypeptide via nucleic acid expression via an expression vector, for use in a method of treating diseases associated with abnormal levels of BGA and/or LacCer and characterized by angiogenesis/neovascularization, by administering the pharmaceutical composition comprising an inhibitory β-1,4-GalT-V antibody as applied to claim 64 above.
The combination of Rossi/Chatterjee/Chatterjee-2018/MM does not teach that the pharmaceutical composition comprises a peptide comprising at least 80% (instant claims 10 and 28) or 90% (instant claims 11 and 28) identity to instant SEQ ID NO: 5 (i.e., IGAQVYEQVLRSAYAKRNSSVND).
Chatterjee-2018 additionally teaches immunohistochemical localization of GAB in human CRC tissue using a mouse monoclonal antibody raised against a GalT-V synthetic peptide of instant SEQ ID NO: 5—IGAQVYEQVLRSAYAKRNSSVND). Thus, Chatterjee-2018 teaches the anti-BGA antibody is produced via administration in a subject to generate an immune response and antibody production (instant claim 40).
Chatterjee-2018 does not teach that the administration is therapeutic (instant claim 40).
Chatterjee-2006 teaches methods for treatment proliferative disorders involving angiogenesis and related to angiogenesis, including cancer, coronary heart disease, tumor metastasis, inflammatory vascular disease, inflammation, ischemia-reperfusion injury, hypertension or diabetes; and for treatment of disorders related to tissue degradation related to angiogenesis, including, for example, intrauterine growth of a fetus, systemic sclerosis, wound healing, ischemia, reperfusion injury, diabetes, coronary artery disease, tumor growth (p.5, para.5). Chatterjee-2006 teaches that
Lactosylceramide (LacCer) is a member of the glycosphingolipid (GSL) family that is ubiquitously present in mammalian tissues and plays a pivotal role as a precursor for the synthesis of complex GSLs (p.4, para.3). Chatterjee-2006 teaches that LacCer is
a member of the neutral glycosphingolipid family and plays a pivotal role by virtue of
serving as a precursor for the biosynthesis of gangliosides such as monosialoganglio- side GM3, disialoganglioside GD3 as well as globotriosylceramide and LacCer sulfate; and, that while these glycosphingolipids have been shown to impart diverse biological functions, LacCer by its own right, has been implicated in cell proliferation, cell adhesion and cell migration; events that are collectively required for angiogenesis; and, additionally teaches that LacCer was found to induce PECAM-1 gene/protein expression, which is a pre-requisite to initiate angiogenesis (p.3, para.3). Chatterjee-2006 teaches pharmaceutical compositions comprising therapeutically effective amounts of VEGF pathway inhibitors, wherein the pathway comprises the interaction or involvement of one or more of LacCer synthase, VEGF, VEGFR, PECAM-1, PLA2, and LacCer (p.6, para.3). which includes(p.5, para.6; p.24, para.1). Chatterjee-2006 further teaches that inhibitors of the VEGF pathway include PECAM-1, LacCer, or LacCer synthase/BGA antibodies, including antibodies specific for GalT-V peptide sequence encoded by instant claim SEQ ID NO: 5 (p.26, para.2); and, inhibitors comprise peptides or fragments thereof for these proteins (p.27, para.1; claims 1, 8, 11, 31, and 33).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date to further combine the teachings of Rossi/Chatterjee/Chatterjee-2018/MM with the teachings of Chatterjee-2006 by modifying the pharmaceutical composition comprising an anti-BGA antibody for inhibiting BGA/LacCer production in order to treat disease (taught by Rossi/Chatterjee/Chatterjee-2018/MM) by additionally including an anti-angiogenic BGA peptide (taught by Chatterjee-2006) of amino acid sequence IGAQVYEQVLRSAYAKRNSSVND in order to generate an immune response (taught by Chatterjee-2018), in order to arrive at the instantly claimed invention because the combination of prior art teachings leads to a predictable beneficial result of treating diseases associated with degeneration and angiogenesis (taught by MM and Chatterjee-2006). One of ordinary skill in the art would have a reasonable expectation of success because Chatterjee-2018 teaches that the IGAQVYEQVLRSAYAKRNSSVND peptide sequence is immunogenic; and, Chatterjee-2006 teaches that angiogenic inhibitors include peptides or fragments from LacCer synthase/BGA.
Allowable Subject Matter
Instant SEQ ID NOs: 3 and 4 at 100% identity are free and clear of the prior art.
The following is a statement of reasons for the indication of allowable subject matter:
The closest prior art for instant SEQ ID NO: 4 is provided by Rossi SEQ ID NO: 17 as described above, which encodes for an amino acid sequence that shares 97.1% identity (see below):
[AltContent: textbox (Instant SEQ ID NO: 4 vs Rossi SEQ ID NO: 17 variable light chain region
[img-media_image2.png])]
[AltContent: textbox (Instant SEQ ID NO: 3 vs Verona SEQ ID NO: 153 variable heavy chain region
[img-media_image4.png])]The closest prior art for instant SEQ ID NO: 3 is provided by Verona, et al.—US20170121409A1 (publication date: 05/04/2017; effective filing date: 11/03/2015) SEQ ID NO: 153, which encodes for an amino acid sequence that shares 84.7% identity (see below):
Conclusion
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/JAMI MICHELLE GURLEY/Examiner, Art Unit 1647
/JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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