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 .
Claim Status
1. Claims 1-15 are currently pending and under examination.
Priority
2. Application claims the benefit of PCT/KR2022/010337 filed on 7/15/2022 which claims the benefit of KR10-2021-0092822 filed on 7/15/2021 and KR10-2022-0010867 filed on 1/25/2022, and KR10-2022-0085650 filed on 7/12/2022. No certified copies of any of the foreign applications have been received. Priority is granted to PCT/KR2022/010337 and the effective filing date of 7/15/2022.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
3. Claims 2-3 and 9-10 are 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.
Regarding claims 2-3, the claims recite the VH of SEQ ID NO:1 with the specific amino acid sequences Y98 and Y99 containing substitutions. As demonstrated below, SEQ ID NO:1 have a “RG” at positions 98 and 99 followed by YYYY at positions 100-103. For the sake of compact prosecution, examiner will consider the Y's at positions 102 and 103 to be the substituted Ys at 98 and 99, respectively, based on Figure 2 and other guidance in the instant specification on page 27 [158]-[162]. Please amend the claims to recite the correct Ys or submit a new SEQ ID NO:1 that is within alignment of Figure 2.
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Regarding claims 9-10, the claims recite the PTPsigma-derived protein comprises amino acid sequence positions 30-231 of a PTPsigma protein with claim 10 further defining the protein where one or more leucines are substituted with asparagine. The claims are indefinite because there is no amino acid structure cited to reference for what the “amino acid sequence positions of 30-231 of a PTPsigma protein” is referring to, and because there is no amino acid sequence structure it is unclear what leucine can be substituted for an asparagine. For the sake of compact prosecution, the examiner will use SEQ ID NO: 3 from the specification for the “30 to 231 of a PTPsigma protein” based on guidance from the specification on page 17 [93] and [94]. Please amend claim 8 in compliance with the 112(a) rejection below to recite SEQ ID NO:3 to overcome this rejection.
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.
4. Claims 1-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a WRITTEN DESCRIPTION rejection.
The claims are drawn to an anti-human transferrin receptor (hTfR) antibody comprising a heavy chain variable region (VH) of SEQ ID NO: 1 and a light chain variable region (VL) of SEQ ID NO: 2, wherein one or more tyrosines (Y) in the amino acid sequence of SEQ ID NO: 1 and 2 are substituted with alanine (A) or histidine (H).
Claim 6 is drawn to a multi-specific antibody comprising a first binding domain that binds human transferrin receptor comprising the VH and VL as described above and a second binding domain that binds to a target molecule.
Claims 7-8 further recite a long list of potential target molecules and protein tyrosine phosphatase sigma (PTPsigma)-derived protein with no amino acid sequence structure for any of the listed target molecules.
Thus, the claims encompass an antibody by the function of binding anti-human transferrin receptor and a partial amino acid sequence of a VH and VL of SEQ ID NOs: 1 and 2 with one or more of any of the Y's in either sequence substituted for A or H. Thus, the claims encompass a vast genus of antibody variants comprising the VH and VL of SEQ ID NOs: 1 and 2 with any Y amino acids substituted for an A or H and required to bind hTfR.
Thus, the claims also encompass a multi-specific antibody comprising the first binding domain comprising the antibody above and a second antigen-binding domain that functions to bind a target molecule with a further list of potential targets including PTPsigma-derived protein with no amino acid structure cited. Thus, the claims encompass a vast genus of multi-specific antibody variants comprising the hTfR VH and VL regions as described above and a second binding domain required to bind a target molecule with no amino acid sequence structure.
The instant specification discloses 4 highly homologous species of VH chain that bind hTfR: a WT chain, a Y27H chain with one substitution at Y27 substituted for H, a Y98A chain with one substitution at Y102 substituted for an A, and a Y99H chain with one substitution at Y103 substituted for an H. The instant specification discloses 2 homologous VL chains that bind hTfR: a WT chain containing no amino acid substitutions and a Y94A chain with one substitution at Y94 substituted for an A. (See preparative example 1, pgs. 26-27, also SEQ ID NOs:1-8).
The instant specification discloses Figure 2 which is a schematic diagram of the VH represented by SEQ ID NO:1. Figure 2 discloses the CDR regions of the VH and indicates that other than the Y's at position Y27, Y98, and Y99 which were substituted and demonstrated to maintain binding function, CDR1 contains a Y at position 32, CDR2 contains a Y at position 59, and CDR3 contains Y's at positions 96, 97, and 102 that were not substituted for an A or H and demonstrated the antibody maintained binding to hTfR.
The instant specification discloses 2 highly homologous binding domains that bind PTPsigma-derived protein: a WT sequence and a 2N sequence with 2 leucines at positions 126 and 158 substituted for a N. (See Experimental Example 4, pgs. 38-40).
Thus, the instant specification discloses one anti-hTfR antibody with a complete VH region of SEQ ID NO:1 with three structurally distinct VH species comprising a specific amino acid substitution of either Y27H, Y102A, and Y103H and a complete VL region of SEQ ID NO:2 with one structurally distinct VL species with one amino acid substitution of Y94A that functions to bind hTfR. The instant specification further discloses one complete anti-PTPsigma-derived protein binding domain of SEQ ID NO:3 with one structurally distinct species comprising 2 specific amino acid substitutions of Ls at positions 126 and 158 for Ns. The specification fails to disclose any other Ys within the VH or VL amino acid sequences of SEQ ID NOs: 1 or 2 that can be substituted for either A or H and still possess the function of binding hTfR. The specification fails to disclose any other anti-PTPsigma-derived protein amino acid sequences or amino acid substitutions of Ls to Ns that can be altered and still possess the function of binding PTPsigma-derived protein.
To provide adequate written description and evidence of possession of the claimed antibody genus, the instant specification can structurally describe representative antibody variants that function to bind hTfR or PTPsigma-derived protein, or describe structural features common to the members of the genus, which features constitute a substantial portion of the genus. Alternatively, the specification can show that the claimed invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics (see University of California v. Eli Lilly and Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) and Enzo Biochem, Inc. V. Gen-Probe Inc.). A disclosure that does not adequately describe a product itself logically cannot adequately describe a method of using that product.
In the case of the invention of the hTfR antibody, the only factor present in the claims is a recitation of the antibody function, “anti-hTfR”, and partial sequence structure as stated above. The instant specification fails to describe structural features common to the members of the antibody genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative antibody variant sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for the antibodies disclosed in the specification through SEQ ID NOs:1-8, the specification fails to disclose structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequence variants for the genus of antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed antibodies.
The claims broadly encompass any sequence variant having a substitution of any Ys to either H or A within SEQ ID NOs: 1 and 2 that functions to bind hTfR. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the VH or VL regions that can be altered and still maintain hTfR binding. Given the well-known high level of polymorphism of antibody binding sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single hTfR antibody comprising SEQ ID NOs: 1 and 2 to the structure of any variants required to bind hTfR as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
In this case of the multi-specific antibody, the only factor present in the claims is a recitation of the antibody function, “anti-hTfR” and a second binding domain that binds to a target molecule, and further defines the second domain as targeting a list of potential target molecules including PTPsigma-derived protein and no amino acid sequence structure. The instant specification fails to describe structural features common to the members of the multi-specific antibody genus, which features constitute a substantial portion of the genus because the instant specification fails to disclose representative binding domain sequences that function as claimed. A definition by function does not suffice to define the genus because it is only an indication of what the antibody does, rather than what it is. Other than for the amino acid sequences disclosed in the specification through SEQ ID NOs:1-8 and 14-17, the specification fails to disclose structural features coupled to the claimed functional characteristics. The instant specification fails to describe a representative number of antibody sequence variants for the genus of multi-specific antibodies that function as claimed. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus required to make the claimed antibodies.
The claims broadly encompass multi-specific antibodies comprising any sequence variant having a substitution of any Y to either H or A within SEQ ID NO: 1 and 2 that functions to bind hTfR and a second binding domain that functions to bind a broad list of target molecules with no recited amino acid structure including PTPsigma-derived protein. Applicants have not established any reasonable structure-function correlation with regards to the sequences in the binding domain that can be altered and still maintain PTPsigma-derived protein binding function. Given the well-known high level of polymorphism of antigen binding sequences and structure, the skilled artisan would not have been in possession of the vast repertoire of multi-specific antibodies encompassed by the claimed invention. One could not reasonably or predictably extrapolate the structure of a single multi-specific antibody comprising an anti-hTfR binding domain and a second binding domain that binds to a target molecule, including PTPsigma-derived protein, to the structure of any variants as broadly claimed. Therefore, one could not readily envision members of the broadly claimed genus.
Although Applicants may argue that it is possible to screen for antibodies or binding domains that bind hTfR or PTPsigma-derived protein and function as claimed, the court found in (Rochester v. Searle, 358 F.3d 916, Fed Cir., 2004) that screening assays are not sufficient to provide adequate written description for an invention because they are merely a wish or plan for obtaining the claimed chemical invention. “As we held in Lilly, “[a]n adequate written description of a DNA … ‘requires a precise definition, such as by structure, formula, chemical name, or physical properties,’ not a mere wish or plan for obtaining the claimed chemical invention.” 119 F.3d at 1566 (quoting Fiers, 984 F.2d at 1171). For reasons stated above, that requirement applies just as well to non-DNA (or RNA) chemical inventions.” Knowledge of screening methods provides no information about the structure of any future antibodies yet to be discovered that may function as claimed. The hTfR or PTPsigma-derived protein antigen provides no information about the structure of an antibody that binds to it.
Given the lack of representative examples to support the full scope of the claimed variant antibodies, and lack of reasonable structure-function correlation with regards to the unknown variable sequences in the VH and VL regions that provide hTfR-binding function; and given the lack of representative examples to support the full scope of the claimed variant multi-specific antibodies, and lack of reasonable structure-function correlation with regards to the binding domains that provide PTPsigma-derived protein-binding function, the present claims lack adequate written description. Thus, the specification does not provide an adequate written description of antibody variants that bind hTfR or binding domains that bind PTPsigma-derived protein that is required to practice the claimed invention.
Examiner Suggestion: Examiner suggests amending claim 1 to recite:
“An anti-human transferrin receptor antibody comprising a heavy chain variable region (VH) of SEQ ID NO: 1 and a light chain variable region (VL) of SEQ ID NO: 2, wherein the antibody further comprises an amino acid substitution selected from the group consisting of Y27H in SEQ ID NO:1, Y102A in SEQ ID NO:1, Y103H in SEQ ID NO: 1 and Y94A in SEQ ID NO:2
Amend claim 6 to recite:
“A multi-specific antibody comprising one or more first binding domains that bind to a human transferrin receptor (hTfR) and one or more second binding domains that bind to a target molecule, wherein the first binding domain comprises a heavy chain variable region (VH) of SEQ ID NO: 1 and a light chain variable region (VL) of SEQ ID NO: 2, wherein the first binding domain further comprises an amino acid substitution selected from the group consisting of Y27H in SEQ ID NO:1, Y102A in SEQ ID NO:1, Y103H in SEQ ID NO:1 and Y94A in SEQ ID NO:2
Cancel claim 7.
Amend claim 8 to recite:
“The multi-specific antibody according to claim 6, wherein the second binding domain comprises a protein tyrosine phosphatase sigma (PTPsigma)-derived protein comprising the amino acid sequence of SEQ ID NO:3.”
5. Claims 14-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a brain disease by administering a multi-specific antibody comprising a first binding domain of an anti-hTfR antibody comprising SEQ ID NO:1 and SEQ ID NO:2 with amino acid substitutions at either Y27H of SEQ ID NO:1, Y98A of SEQ ID NO:1, Y99H of SEQ ID NO:1, or Y94A of SEQ ID NO:2 and the PTPsigma-derived protein comprising the amino acid sequences of SEQ ID NO: 3, does not reasonably provide enablement for the prevention of brain diseases with an antibody or multi-specific antibody, or the treatment of brain diseases with a multi-specific antibody comprising SEQ ID NOs: 1 and 2 with one or more Ys substituted for an A or H and a second binding domain to any target. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
The claims are drawn to a method of preventing or treating brain diseases comprising administering a multi-specific antibody comprising a first binding domain comprising a VH of SEQ ID NO:1 and a VL of SEQ ID NO:2 with one or more Ys in either sequence being substituted for an A or H.
The specification discloses 4 variant hTfR antibodies that all demonstrate decreased binding affinity to hTFR as compared to the WT as observed in Table 3 from pages 32-33, copied below.
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The specification discloses in experimental example 4 an in vitro blood-brain barrier permeability assay that the Y27H mutation demonstrated increased blood brain permeability over the wild-type antibody as observed in Fig. 9 below.
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The specification further discloses in experimental example 4 another in vitro blood-brain barrier permeability assay that demonstrates the multi-specific antibody comprising the anti-hTfR Y27H and PTPsigma antibody which demonstrated significantly increased blood brain barrier over the wild-type anti-hTfR multi-specific antibody as observed in Figure 11 below.
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The specification on page 6 [31] further discloses the hTfR antibodies have been specifically designed to have reduced binding affinity to make them more efficient at transcytosis through the cells of the blood brain barrier.
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The specification also discloses in Experimental Example 5 a neurite growth assay which demonstrates the bispecific antibodies including the PTPsigma-derived protein (comprising the amino acid sequences of SEQ ID NO:3), both wild type and 2N variant possessing the ability to treat a neuroblastoma cell line in vitro as demonstrated in Figure 12 below. However, the specification fails to provide any working examples of the prevention of brain diseases through the administration of the antibodies.
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Neves, et al. (Trends in biotechnology, 2016, 34(1):36-48) teaches that receptor mediated transport (RMT) is an important strategy for treating brain disorders by transporting specific endogenous large molecules, like antibodies, across the blood brain barrier and transferrin receptor (TfR) is a widely known and used method for successful RMT. (See Neves, pg. 38 “Strategies for Crossing the BBB”). Neves also teaches that TfR antibodies with lower affinity for TfR have an increased likelihood of crossing the BBB due to the ability to release from the TfR once transcytosis has occurred. (See Neves, pg. 40 paragraph 2). Neves further teaches that while some antibodies that cross the BBB have shown promise of preventing inherited dementia, there is no indication they have been able to prevent brain malignancies, non-degenerative genetic disorders, or brain and spinal cord injuries. (See Neves, pg. 46 Paragraph 3).
Altschuler et al. (Biochemistry, 2010, 75(13):1584-1605) teaches that the process of mutation to regulate antibodies binding affinity is unpredictable and requires the experimentation of obtaining the mutated antibody and testing the binding affinity. (See Altschuler, pg. 1594, column 1, paragraph 3).
One cannot extrapolate the disclosure of the specification to the enablement of the claims because the specification only demonstrates the increased permeability of a variant antibody demonstrating decreased affinity for hTfR. Guidance from the specification indicates that regulating the affinity of the TfR antibody is part of the strategy to increase its permeability. Prior art teaches that regulating the affinity of an antibody is unpredictable and requires the generation of antibody variants through pointed amino acid substitutions and testing of the affinity to prove success. Further, prior art teaches that a decreased binding affinity increases the antibodies permeability across the BBB and the specification demonstrates the 4 variant antibodies to hTfR have decreased binding affinity but fails to identify any other amino acid substitutions of a Y in SEQ ID NOs: 1 or 2 for an A or H that leads to decreased affinity leading to an increased likelihood in permeability of the BBB.
One cannot extrapolate the disclosure of the specification to the enablement of the claims because the specification does not provide guidance or examples of substitutions of Y to A or H in SEQ ID NOs:1 and 2, outside the listed variants, that can be made and still maintain the ability to cross the BBB to treat brain disorders. One cannot extrapolate the disclosure of the specification to the enablement of the claims because the specification does not provide any working examples of the prevention of a brain disorder or disease as listed in claim 15.
Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that the multi-specific anti-hTfR antibody comprising SEQ ID NOs: 1 and 2 with one or more amino acid substitutions of Y for an A or H and a second binding domain that binds to a target molecule, outside of those listed above, will predictably function as claimed.
Therefore, in view of the state of the art, the quantity of experimentation necessary, the breadth of the claims, lack of guidance in the specification, and the absence of working examples, it would require undue experimentation for one skilled in the art to practice the invention as broadly claimed.
Examiner Suggestion: Amend claims 6 and 8 as described above under the written description rejection, amend claim 14 to depend from claim 8, and remove “preventing” from claims 14 and 15.
Claim Rejections - 35 USC § 103
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.
6. Claims 1-7 and 11-15 are rejected under 35 U.S.C. 103 as being unpatentable over Rueger (WO2015/101588 A1, pub. 7/9/2015) in view of Neves (Trends in Biotechnology, 2016, 34(1):36-48).
Regarding claims 1-5, Rueger discloses a module for delivering a brain effector entity across the blood brain barrier comprising an antibody for human transferrin receptor comprising the sequences of SEQ ID NOs:1 and 2. (See Rueger, pg. 22 lines 27-29, pg. 24 lines 13-15 SEQ ID NOs:11 and 12, see alignment below). Rueger discloses the anti-hTfR antibody can be conjugated to a neurological drug. (See Rueger, pg. 3 lines 23-27). Rueger discloses the anti-hTfR antibody can be humanized. (See Rueger, pg. 39 lines 1-2).
Regarding claim 6, Rueger discloses multi-specific antibodies comprising binding domains for the anti-hTfR antibody from above and another antigen. (See Rueger, pg. 53 lines 22-26).
Regarding claims 7 and 11-12, Rueger discloses the multi-specific antibody can be the first binding domain can be an antibody fragment of a Fab or a scFv and the second binding domain comprises a target molecule including BACE1, gamma-secretase, Abeta, EGFR, tau, ApoE4, alpha-synuclein, CD20, Huntington protein, prion protein, LRRK2, APP, p75NTR, and caspase 6 and the first binding domain and second binding domain are linked to an Fc region. (See Reuger, pg. 3 line 1-pg. 4 line 16).
Regarding claim 13, Rueger discloses cysteine engineering for the antibodies to enable them to be conjugated to other moieties including drug moieties or linker drug moieties. (See Rueger, pg. 81 lines 2-8).
Regarding claims 14-15, Rueger discloses that the anti-TfR antibody and second binding domain can be used to treat brain disorders including Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. (See Rueger, pg. 5 lines 21-23 and pg. 19 lines 9-31).
Rueger’s does not disclose the SEQ ID NOs: 1 and 2 comprising one or more Ys substituted for an A or H.
Neves teaches strategies for improving the permeability of antibodies crossing the blood brain barrier including using amino acid substitutions to decrease the binding affinity of an endothelial binding receptor, like transferrin receptor, allowing for an easier release of the antibody molecule into the brain environment. In particular, Neves teaches that alanine mutations within the CDR regions of anti-TfR antibodies were successful at decreasing the binding affinity. (See Neves, pg. 40 paragraph 2).
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to combine the disclosed antibody and multi-specific antibody of Rueger with the teachings of Neves to produce the anti-hTfR antibody and multi-specific antibody comprising the Y98A variant of SEQ ID NO:1 of the present claimed invention. It would have been obvious because the anti-hTfR antibody of Rueger of SEQ ID NOs: 11 and 12 are known in the art, Neves teaches that alanine substitutions in the CDR regions are successful at decreasing the binding affinity for antibody binding in anti-hTfR antibodies which makes it more effective at crossing the blood brain barrier, and the Y98A substitution occurs at the CDR3 region of the VH of SEQ ID NO:1 as disclosed in Figure 2 of the instant specification. There would be a reasonable expectation of success because Neves teaches the antibody mutation of Y27 being substituted for an A in the CDR region would have decreased the binding affinity. Therefore, it would have been obvious for a person of ordinary skill in the art to combine the disclosed antibody and multi-specific antibody of Rueger with the teachings of decreasing antibody binding affinity of Neves with a reasonable expectation of success at producing the anti-hTfR antibody comprising a Y98A substitution of SEQ ID NO: 1 to treat brain disorders of the present claimed invention.
SEQ ID NO: 1 100% matches SEQ ID NO: 11 (Rueger):
WO2015101588-A1.
XX
CC PD 09-JUL-2015.
XX
CC PF 29-DEC-2014; 2014WO-EP079353.
XX
PR 06-JAN-2014; 2014WO-CN070183.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Rueger P, Tiefenthaler G, Moessner E, Niewoehner J, Hugenmatter A;
CC PI Shao C, Ros F, Xu G;
XX
DR WPI; 2015-388518/49.
XX
CC PT New monovalent blood brain barrier shuttle module comprises brain
CC PT effector entity, optionally linker and exactly one (monovalent) binding
CC PT entity which binds to blood brain barrier receptor, useful for treating
CC PT neurological disorder.
XX
CC PS Disclosure; SEQ ID NO 11; 113pp; English.
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
2 637 100.0 137 BAE62961 -- 2 Anti-transferrin receptor monoclonal antibody VH region, SEQ ID 21.
ALIGNMENT:
Query Match 100.0%; Score 637; Length 137;
Best Local Similarity 100.0%;
Matches 118; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGENLEWIGRINPHNGGTDY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 20 EVQLQQSGPELVKPGASMKISCKASGYSFTGYTMNWVKQSHGENLEWIGRINPHNGGTDY 79
Qy 61 NQKFKDKAPLTVDKSSNTAYMELLSLTSEDSAVYYCARGYYYYSLDYWGQGTSVTVSS 118
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 80 NQKFKDKAPLTVDKSSNTAYMELLSLTSEDSAVYYCARGYYYYSLDYWGQGTSVTVSS 137
SEQ ID NO: 2 100% matches SEQ ID NO: 12 (Rueger):
WO2015101588-A1.
XX
CC PD 09-JUL-2015.
XX
CC PF 29-DEC-2014; 2014WO-EP079353.
XX
PR 06-JAN-2014; 2014WO-CN070183.
XX
CC PA (HOFF ) HOFFMANN LA ROCHE & CO AG F.
CC PA (HOFF ) HOFFMANN LA ROCHE INC.
XX
CC PI Rueger P, Tiefenthaler G, Moessner E, Niewoehner J, Hugenmatter A;
CC PI Shao C, Ros F, Xu G;
XX
DR WPI; 2015-388518/49.
XX
CC PT New monovalent blood brain barrier shuttle module comprises brain
CC PT effector entity, optionally linker and exactly one (monovalent) binding
CC PT entity which binds to blood brain barrier receptor, useful for treating
CC PT neurological disorder.
XX
CC PS Disclosure; SEQ ID NO 12; 113pp; English.
XX
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
2 569 100.0 128 AAR41686 -- 3 128.1 VL encoded by plasmid pAH4611.
ALIGNMENT:
Query Match 100.0%; Score 569; Length 128;
Best Local Similarity 100.0%;
Matches 107; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 GQIVLTQSPAIMSASPGEKVTMTCSASSSIDYIHWYQQKSGTSPKRWIYDTSKLASGVPA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 22 GQIVLTQSPAIMSASPGEKVTMTCSASSSIDYIHWYQQKSGTSPKRWIYDTSKLASGVPA 81
Qy 61 RFSGSGSGTSYSLTISSMEPEDAATYYCHQRNSYPWTFGGGTRLEIR 107
|||||||||||||||||||||||||||||||||||||||||||||||
Db 82 RFSGSGSGTSYSLTISSMEPEDAATYYCHQRNSYPWTFGGGTRLEIR 128
7. Claims 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Rueger (WO2015/101588 A1, pub. 7/9/2015) and Neves (Trends in Biotechnology, 2016, 34(1):36-48) as applied to claims 1-7 and 11-15 above, and further in view of Ryu et al. (WO/2022/060151, effectively filed 9/18/2020).
Rueger and Neves disclose the limitations of claim 6 as discussed above.
Rueger and Neves do not disclose a second binding domain of a protein tyrosine phosphatase sigma (PTPsigma)-derived protein of SEQ ID NO:3 wherein one or more of leucines (L) are substituted with asparagine (N).
Ryu discloses a PTPsigma protein for use with treating brain diseases and disorders including traumatic brain injury, Alzheimer’s disease, Parkinson’s disease. (See Ryu pg. 5 [30]-[32]). Ryu discloses the amino acid sequence of a PTPsigma protein that is identical to SEQ ID NO: 3. (SEQ ID NO: 1, see alignment below). Ryu teaches the solubility of the PTPsigma protein can be improved to treat subjects with a higher dose by substituting specific amino acid including leucine, to other amino acids including asparagine. (See Ryu, pg. 5 [16]-[19], and pg. 6 [34]). Ryu discloses the amino acid sequence of SEQ ID NO:3 with a L126A and L156A that is identical to the 2N variant of PTPsigma protein of the instant specification. (See Ryu, Example Fig. 26b, also alignment below).
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to combine the multi-specific antibody of Rueger and Neves with the disclosed PTPsigma-derived protein disclosed by Ryu for the present claimed invention. It would have been obvious because Ryu teaches that PTPsigma protein is used to target brain disorders and diseases and the multi-specific antibody of Rueger and Neves allows for increased permeability to cross the BBB to treat brain disorders. It would have a reasonable expectation of success because Rueger teaches the antibody can be in a multi-specific form to allow for the transfer of neurodrugs to the brain environment and Ryu teaches that the amino acid substitutions allow the PTPsigma protein to be more soluble and can be administered at higher doses. Therefore, it would have been obvious to a person of ordinary skill in the art prior to the effective filing date to combine the multi-specific antibody of Rueger and Neves with the PTPsigma protein as disclosed in Ryu with a reasonable expectation of success at improved drug targeting brain disorders using the multi-specific antibody of the present claimed invention.
SEQ ID NO:3 is 100% identical to SEQ ID NO: 1 (Ryu):
WO2022060151-A1.
XX
CC PD 24-MAR-2022.
XX
CC PF 17-SEP-2021; 2021WO-KR012763.
XX
PR 18-SEP-2020; 2020KR-00120887.
PR 03-SEP-2021; 2021KR-00117865.
XX
CC PA (UHYG ) UNIV HANYANG IUCF-HYU.
XX
CC PI Ryu SE, Jang HH, Kim MB, Park SH;
XX
DR WPI; 2022-429703/029.
XX
CC PT New fusion protein comprising protein derived from protein tyrosine
CC PT phosphatase sigma (PTP-sigma) being linked to two chains constituting
CC PT fragment crystallizable domain derived from immunoglobulin, promoting
CC PT blood stem cell growth and treating PTP-sigma-mediated disease e.g.
CC PT mania.
XX
CC PS Example; SEQ ID NO 1; 52pp; Korean.
XX
SQ Sequence 202 AA;
Query Match 100.0%; Score 1050; Length 202;
Best Local Similarity 100.0%;
Matches 202; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 EEPPRFIKEPKDQIGVSGGVASFVCQATGDPKPRVTWNKKGKKVNSQRFETIEFDESAGA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 EEPPRFIKEPKDQIGVSGGVASFVCQATGDPKPRVTWNKKGKKVNSQRFETIEFDESAGA 60
Qy 61 VLRIQPLRTPRDENVYECVAQNSVGEITVHAKLTVLREDQLPSGFPNIDMGPQLKVVERT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 VLRIQPLRTPRDENVYECVAQNSVGEITVHAKLTVLREDQLPSGFPNIDMGPQLKVVERT 120
Qy 121 RTATMLCAASGNPDPEITWFKDFLPVDPSASNGRIKQLRSGALQIESSEETDQGKYECVA 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 RTATMLCAASGNPDPEITWFKDFLPVDPSASNGRIKQLRSGALQIESSEETDQGKYECVA 180
Qy 181 TNSAGVRYSSPANLYVRVRRVA 202
||||||||||||||||||||||
Db 181 TNSAGVRYSSPANLYVRVRRVA 202
SEQ ID NO:3 with L126A and L156A substitutions from Ryu:
WO2022060151-A1.
XX
CC PD 24-MAR-2022.
XX
CC PF 17-SEP-2021; 2021WO-KR012763.
XX
PR 18-SEP-2020; 2020KR-00120887.
PR 03-SEP-2021; 2021KR-00117865.
XX
CC PA (UHYG ) UNIV HANYANG IUCF-HYU.
XX
CC PI Ryu SE, Jang HH, Kim MB, Park SH;
XX
DR WPI; 2022-429703/029.
XX
CC PT New fusion protein comprising protein derived from protein tyrosine
CC PT phosphatase sigma (PTP-sigma) being linked to two chains constituting
CC PT fragment crystallizable domain derived from immunoglobulin, promoting
CC PT blood stem cell growth and treating PTP-sigma-mediated disease e.g.
CC PT mania.
XX
CC PS Example; Fig 26b; 52pp; Korean.
XX
XX
SQ Sequence 458 AA;
Query Match 98.7%; Score 1036; Length 458;
Best Local Similarity 99.0%;
Matches 200; Conservative 0; Mismatches 2; Indels 0; Gaps 0;
Qy 1 EEPPRFIKEPKDQIGVSGGVASFVCQATGDPKPRVTWNKKGKKVNSQRFETIEFDESAGA 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 22 EEPPRFIKEPKDQIGVSGGVASFVCQATGDPKPRVTWNKKGKKVNSQRFETIEFDESAGA 81
Qy 61 VLRIQPLRTPRDENVYECVAQNSVGEITVHAKLTVLREDQLPSGFPNIDMGPQLKVVERT 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 82 VLRIQPLRTPRDENVYECVAQNSVGEITVHAKLTVLREDQLPSGFPNIDMGPQLKVVERT 141
Qy 121 RTATMLCAASGNPDPEITWFKDFLPVDPSASNGRIKQLRSGALQIESSEETDQGKYECVA 180
||||| ||||||||||||||||||||||||||||||| ||||||||||||||||||||||
Db 142 RTATMNCAASGNPDPEITWFKDFLPVDPSASNGRIKQNRSGALQIESSEETDQGKYECVA 201
Qy 181 TNSAGVRYSSPANLYVRVRRVA 202
||||||||||||||||||||||
Db 202 TNSAGVRYSSPANLYVRVRRVA 223
Conclusion
9. Claims 1-15 are rejected.
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/LINDSAY DUNN/Examiner, Art Unit 1642
/Laura B Goddard/Primary Examiner, Art Unit 1642
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