Office Action 1: Non-Final Rejection (2024-08-27)
Rejection types: 112 - Written Description/Enablement

CLAIMS:
Amendments to the Claims:

This listing of claims will replace all prior versions, and listings, of claims in the application: Listinq of Claims:

1\. (currently amended) A monoclonal antibody or antigen-binding fragment thereof that specifically \[\[bind\]\] binds to the TRBV-9 family beta-chain region of the human T cell receptor, comprising a heavy chain variable domain, the amino acid sequence of which is shown in SEQ ID No: 16 and a light chain variable domain, the amino acid sequence of which is shown in SEQ ID No: 18.

2\. (currently amended) \[\[A \]\]The monoclonal antibody according to Claim 1, which includes a heavy chain having the amino acid sequence of SEQ ID No: 20 and a light chain having the amino acid sequence of SEQ ID No: 22.

3\. (currently amended) \[\[A \]\]The monoclonal antibody according to Claim\[\[s\]\] 2, which is a full-length IgG antibody.

4\. (currently amended) A nucleic acid that encodes a monoclonal antibody or antigen- binding fragment thereof according to Claim\[\[s\]\] 1\[\[-3\]\], wherein the antibody or antigen binding fragment thereof specifically binds to the TRBV9 family beta-chain region of the human T receptor.

5\. (original) An expression vector containing a nucleic acid according to Claim 4.
6\. (currently amended) A method of obtaining a host cell for producing an antibody or antigen-binding fragment thereof that specifically binds to the TRBV-9 family beta-chain reqion of the human T cell receptor, comprising a heavy chain variable domain, the amino acid sequence of which is shown in SEQ ID No: 16 and a light chain variable domain, the amino acid sequence of which is shown in SEQ ID No: 18 3-comprising co-transformation of a cell with a vector according to Claim 5.

7\. (currently amended) A host cell for obtaining an antibody or antigen-binding fragment thereof that specifically binds to the TRBV-9 family beta-chain region of the human T cell receptor, comprising a heavy chain variable domain, the amino acid sequence of which is shown in SEQ ID No: 16 and a liqht chain variable domain, the amino acid sequence of which is shown in SEQ ID No: 18 omprising a nucleic acid according to Claim 4.

8\. (currently amended) A method of obtaining an antibody or antigen-binding fragment thereof according to \[\[any of \]\]Claim\[\[s\]\] 1\[\[-3\]\], comprising culturing a host cell for obtaining a monoclonal antibody or antigen-binding fragment thereof that specifically bind to the TRBV-9 family beta-chain region of the human T cell receptor, comprising a heavy chain variable domain, the amino acid sequence of which is shown in SEQ ID No: 16 and a light chain variable domain, the amino acid sequence of which is shown in SEQ ID No:
18
 in a culture medium under conditions ensuring the production of said antibody, followed by isolation and purification of the obtained antibody.

9\. (currently amended) A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof according to \[\[any of \]\]Claim\[\[s\]\] 1\[\[-3\]\] in combination with one or more pharmaceutically acceptable excipients.

10\. (currently amended) \[\[A \]\]The pharmaceutical composition of Claim\[\[ 9\]\] 19, wherein said disease or disorder is selected from the group: ankylosing spondylitis, celiac disease, T cell leukemia, T cell lymphoma.
11\. (currently amended) A pharmaceutical composition , comprising an antibody or antigen-binding fragment thereof according to \[\[any of \]\]Claim\[\[s\]\] 1\[\[-3\]\] and at least in a therapeutically effective amount one other therapeutically active compound.

12\. (currently amended) \[\[A \]\]The pharmaceutical composition of Claim\[\[ 11\]\] 20, wherein said disease or disorder is selected from the group: ankylosing spondylitis, celiac disease, T cell leukemia, T cell lymphoma.

13\. (currently amended) \[\[A \]\]The pharmaceutical composition according to \[\[any of \]\] Claim\[\[s\]\] \[\[11-\]\]12, wherein the other therapeutically active compound is selected from a small molecule, antibody or steroid hormones.

14\. (currently amended) A method for inhibiting the biological activity of the T cell receptor, the beta-chain of which belongs to the TRBV9 family, in a subject in need of such inhibition, comprising administering to the subject an effective amount of an antibody or antigen-binding fragment thereof according to \[\[any of \]\]Claim\[\[s\]\] 1\[\[-3\]\].
15\. (currently amended) A method for treating a disease or disorder mediated by the human T cell receptor bearing the TRBV9 family beta-chain, comprising administering to a subject in need of such treatment an antibody or antigen-binding fragment thereof SVG {EMBED HERE} 0.16 6.5 in a therapeutically effective amount.

16\. (currently amended) \[\[A \]\]The method for treating a disease or disorder according to Claim\[\[ 17\]\] 15, wherein the disease or disorder is selected from the group: ankylosing spondylitis, celiac disease, T cell leukemia, T cell lymphoma.
17- 18. (cancelled)

19\. (new) The pharmaceutical composition according to Claim 9, wherein the composition is for preventing or treating a disease or disorder mediated by the TRBV9 family beta- chain region of the human T receptor.

20\. (new) The pharmaceutical composition according to Claim 11, wherein the composition is for preventing or treating a disease or disorder mediated by the human T cell receptor bearing the TRBV9 family beta-chain.

21\. (new) A method for treating a disease or disorder mediated by the human T cell receptor bearing the TRBV9 family beta-chain, comprising administering to a subject in need of such treatment a pharmaceutical composition according to Claim 9 in a therapeutically effective amount.

22\. (new) The method for treating a disease or disorder according to Claim 21, wherein the disease or disorder is selected from the group: ankylosing spondylitis, celiac disease, T cell leukemia, T cell lymphoma.

23\. (new) A method for treating a disease or disorder mediated by the human T cell receptor bearing the TRBV9 family beta-chain, comprising administering to a subject in need of such treatment a pharmaceutical composition according to Claim 12 in a therapeutically effective amount.

24\. (new) The method for treating a disease or disorder according to Claim 23, wherein the disease or disorder is selected from the group: ankylosing spondylitis, celiac disease, T cell leukemia, T cell lymphoma. page 2 of 6 page 3 of 6 page 4 of 6 page 5 of 6

OFFICE ACTION:
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 .
Status of Claims
The amendment filed 02/17/2022, is acknowledged and has been entered. Claims 1-4, 6-16 have been amended. Claims 17-18 have been cancelled. Claims 1-9, 13-16, and 21-24 are allowed, while Claims 10-12, 19, and 20 are rejected.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. PCT/RU2019/050257, filed on 12/24/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 08/25/2021, 01/16/2023, 05/01/2024, 05/02,2024 are in compliance with the provisions of 37 CFR 1.97.  Accordingly, the information disclosure statement is being considered by the examiner.
Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc.  In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it contains legal phraseology (i.e., relates to a nucleic acid encoding said antibody; a method for preparing said antibody, and use of said antibody).  Correction is required.  See MPEP § 608.01(b).
Drawings
The drawings are objected to because of lack of appropriate labeling of panels and conditions in Figure 3 as well as mislabeling of the Y axis. Additionally, Figure 2 should stand alone and therefore needs to indicate which panel (left or right, please label as A, B) was treated with the MA-042 antibody at what concentration (1pg/ml or 1 ng/ml, respectively). In Figure 3 the Y axis is labeled as “% of dead TRBV9+ cells”, however the specification text reds “number of dead T lymphocytes as a function of MA-042 concentration…” Please clarify by correcting the text to indicate that the measurement is of the fraction of dead cells, not their absolute number).
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 10, 12, 22, and 24 are objected to because of the following informalities: lack of required conjunction (“or”) between the group members listed for disease selection (“wherein said disease or disorder is selected from the group: ankylosing spondylitis, celiac disease, T cell leukemia, T cell lymphoma”).  Appropriate correction is required. Final text should read “wherein said disease or disorder is selected from the group: ankylosing spondylitis, celiac disease, T cell leukemia, T cell OR lymphoma”.
Claim Rejections - 35 USC § 112a
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 10, 12, 19 and 20 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 the treatment of a disease or disorder mediated by TRBV9-bearing T lymphocytes, does not reasonably provide enablement for the prevention of a condition involving the TRBV9 family beta-chain region of the human T receptor.  The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Claim 19 is drawn to the use of the pharmaceutical composition according to claim 9, which comprises an antibody (Ab) or antigen-binding fragment (Fab) thereof according to claim 1 in combination with one or more pharmaceutically acceptable excipients, in the prevention or treatment of a disease or disorder mediated by the TRBV9 family beta-chain region of the human T receptor.
Claim 20 is drawn to the use of the pharmaceutical composition according to claim 11 (comprising an Ab or Fab thereof according to claim 1 and at least in a therapeutically effective amount one other therapeutically active compound) in the prevention or treatment of a disease or disorder mediated by the human T cell receptor bearing the TRBV9 family beta-chain.
Claim 10 is drawn to the pharmaceutical composition presented in claim 19, which originates from claim 9 and defines the pharmaceutical composition as claim 1’s Ab or Fab in combination with one or more excipient, for the specific treatment or prevention of ankylosing spondylitis, celiac disease, T cell leukemia, or T cell lymphoma.
Claim 12 is drawn to the pharmaceutical composition of claim 20, which originates from claim 11 and defines a pharmaceutical composition comprising a combination of claim 1’s antibody or Ag-binding fragment and one other therapeutically active compound in a therapeutically effective amount, for the specific treatment or prevention of ankylosing spondylitis, celiac disease, T cell leukemia, or T cell lymphoma.
The specification does not disclose relevant examples for the assertions made in claims 10, 12, 19, or 20 in that, despite providing guidance towards treatment of disease, significant additional research is required in order to determine how effective the composition(s) in these claims might be used in the prevention of ankylosing spondylitis, celiac disease, T cell leukemia, or T cell lymphoma.
Due to the absence of working examples in the specification, a person having ordinary skill in the art would not be enabled in the use the pharmaceutical composition of either claim 9 or claim 11, as disclosed, to prevent a disease or disorder mediated by the TRBV9 family beta-chain T receptor broadly, or ankylosing spondylitis, celiac disease, T cell leukemia, or T cell lymphoma, more specifically. As such, while the specification provides guidance towards the treatment of one of the aforementioned diseases after onset, there is no disclosure of any evidence that the approach as proposed could be used to prevent any of the mentioned TRBV9-mediated conditions. Furthermore, based on the claim language in claim 20, it appears the applicant is suggesting that TRVB9-bearing T cells are the causative agent of the diseases presented in the group consisting of ankylosing spondylitis, celiac disease, T cell leukemia, T cell lymphoma. If this is the case, then the administration of the pharmaceutical composition described in claim 11, from which claim 20 originates, must prevent the aforementioned disorder. Therefore, the lack of existent working examples in the specifications and the significant amount of additional research, amounting to undue experimentation for one skilled in the art, that would be required to determine how effective the combination of the pharmaceutical compositions disclosed is not commensurate with the content or scope of the disclosure.
Factors to be considered in determining whether undue experimentation is required are summarized in Ex parte Forman 230, USPQ 546 (BPAI 1986). They include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed. In considering the language used in claims 19 and 20 regarding the use of the anti-TRVB9 Ab/Fab in question to treat and prevent disease in the disease models named herein, one must assess what is the state of the art for therapeutic approaches to the prevention and management of autoimmune and oncological disorders.
WO/1990/006758 and WO/1994/005801 disclose monoclonal antibodies against B-chain regions of the human T cell receptor variable domains, belonging to the TRBV5-3/TRBV8-1 and TRBV3-1 families, respectively, that may serve as diagnostic tools and therapeutic treatments for rheumatoid arthritis.  Furthermore, in a model of experimental autoimmune encephalomyelitis (EAE), which is an experimental mouse model mimicking human multiple sclerosis (MS) disease, Zhao and colleagues teach that public TCRB chains can confer susceptibility to autoimmune disease – specifically that TCRβ1 supports recognition of the MOG peptide targeted by autoreactive T cells and that TCRβ2-6 are key players in mediating demyelinating CNS disease (Zhao et al, Sci Rep, 2016). Petersen and colleagues teach that at least two populations of autoreactive T cells that recognize and respond to the DQ8-glia-a1 peptide (found in 95%+ of CD patients) have biased clonotypic repertoires that are composed of TRBV9 chains (Petersen et al, J Immunol, 2015).
Currently, the only effective treatment for celiac disease is a gluten-free diet, which causes inferior quality of life and economic burden, does not always achieve remission, and the improvement of symptoms while on a gluten-free diet is not adequate for diagnosis (Kivelä et al, Nat Rev Gastronterol Hep, 2021 & Silvester et al, Am J Gastroenterol, 2021).  Kivelä and colleagues teach that new molecular insights into pathogenesis of celiac disease have provided targets for novel therapeutic strategies, including gluten sequestration, treatments to reduce the permeability of intestinal epithelial cells, and blockade of transglutaminase 2. Additionally, the state of the art supports the treatment of refractory celiac disease with pharmacological agents that include steroids such as budesonide or prednisone, and while a recent phase 2a trial of an anti-IL-15 antibody failed to reduce the size of the autoreactive T cell population in the intestinal epithelia, there were improvements in secondary endpoints, indicating that immunotherapeutic interventions should be investigated further (Cattasi et al, Lancet, 2022).
Boulos and colleagues teach that state of the art treatments of ankylosing spondylitis include a combination of non-steroidal anti-inflammatory drugs (NSAIDs), disease modifying antirheumatic drugs (DMARDs), biphosphonates, and immunomodulating biologics (Boulos et al, Drugs, 2012). TNF blockers are considered an effective method of addressing both axial disease and include infliximab, etanercept, golimumab, certolizumab, and adalimumab, which can be given as monotherapy or in conjunction with methotrexate (Maksymowych, 2007, Thera Clin Risk Man, 3(6), 1125–1133 and Amaral de Avila Machado et al, Rheumatol Int, 2013 (33:2199-2213).  Yin et al teach that current strategies now focus on direct neutralization of soluble disease-mediating factors such as interleukin17 (IL-17) via humanized antibodies including secukinumab or ixekizumab, which have been shown to produce a significant decrease in clinical disease score (Yin, Y. et al, Arthritis Res Ther 22, 111, 2020). Furthermore, recent teachings instruct on the use of TRBV targeting monoclonal antibodies to eliminate autoaggressive T cells in AS including those against, CD8+ TRBV9-bearing cells (Komech et al, Rheumatology, 2018; Yang et al, Nature, 2022; Britanova et al, Nat Med, 2023).
Taken together, while the state of the art does teach approaches to treatments to improve disease burden and patient quality of life, it does not support any known processes or products that have been successfully evaluated for the prevention of celiac disease or ankylosing spondylitis or other autoimmune diseases such as rheumatoid arthritis or multiple sclerosis.
T cell acute lymphoblastic leukemia/lymphoma (T-ALL) is a type of non-Hodgkin disease that can be categorized as either a lymphoblastic lymphoma (LBL) or acute lymphoblastic leukemia (ALL). Current state of the art for first line treatments include chemotherapy, including dexamethasone, asparaginase, intrathecal chemotherapy, and methotrexate, as taught by Raetz and Teachey (Am Soc Hematol Educ Prog, 2016). Select patients may also be eligible for chemotherapy plus hematopoietic stem cell transplantation (HCT) and/or radiation. Importantly, the art teaches that therapeutic approaches to the elimination of blood T cell malignancies can include targeted elimination of transformed T cell clones via the depletion of these cells based on their TRBV expression. Specifically, Lucero and colleagues teach that in the case of large granular T cell leukemia circulating T cell pool is dominated by a single TRVB clonotype, in the instant case, VB13.3, which could be killed by the administration of therapeutic antibodies (Lucero et al, Clin Cancer Res, 2023).
Immunomodulatory therapies have become of greater interest as more is understood regarding the molecular underpinnings of the pathogenesis of T cell malignancies. Previous art teaches that particular TCR VBs within the T cell repertoire define certain T cell malignancies.  For example, leukemic cell lines including Jurkat cells and Molt-4 cells express VB8 and VB2, respectively and new strategies are being developed to target these monoclonal cells via CAR T cells (Li et al, Nat Comms, 2022). TRBV9 specifically has been documented on the surface of T cells in an experimental murine model of EBV-induced T cell lymphoma (Toyabe et al, Clin Exp Immunol, 2003). However, the state of the art does not teach any current strategies by which TRBV targeting can prevent the malignant transformation of T cells.
The art also teaches the importance of the recent discovery of mutations of NOTCH family members which may contribute to transformation and be targeted by immunotherapies and/or gamma-secretase inhibitors (Litzow & Ferrando, Blood, 2015). Additionally, while recent studies teach the use of adoptive cellular therapy in conjunction with “vaccines” for the treatment of cancer (Hammerich et al, 2019, Nat Med; Ghilardi et al, 2024, Nat Med) these strategies are only used after the diagnosis of transformed blood cells and therefore do not truly address issues of cancer prevention. Therefore, the current state of the art teaches that the development of an Ab/Fab-mediated or CAR-engineered approach to treating certain autoimmune and oncological disorders is predictable, it does not provide rationale for the use of this strategy in the prevention of disease.
In light of the state of the art and the aforementioned references, the specification fails to teach how a persona having ordinary skill in the art might make and use the broadly claimed invention without undue experimentation. Thus, claims 10, 12, 19 and 20 are rejected.
Allowable Subject Matter
The following is a statement of reasons for the indication of allowable subject matter:
Claims 1-9, 11, 13-16, and 21-24 are allowed. Toyabe and colleagues (Clin Exp Immunol, 2003, 135(1):92-97) disclose a TRBV9-binding antibody/antigen-binding fragment (Fab) as well as a nucleic acid encoding the aforementioned protein. Furthermore, this group describes an expression vector, a host cell for producing the Ab/Fab after incorporation of the nucleic acid-containing vector, a method for obtaining said host cell and finally, a method for producing an antibody or an antigen-binding fragment thereof. The authors report that the disclosed antibody/antigen-binding fragment is able to bind to TRBV9 expressed on PBMCs of EBV-infected individuals.
After examination, it is established that the inventions disclosed in independent claims 1, 4-9, 14, and 15 are distinct from those described by Toyabe et al in that the amino acid sequences of the variable domains of the HC and LC of the antibody/antigen-binding fragment in the Clin Exp Immunol publication differ from those reported here in as SEQ ID NO.: 16 and SEQ ID NO.: 18. As such the aforementioned claims and their dependents are novel as they describe a previously unreported ab/Fab with extensive humanization and the ability to bind to the TRBV9 chain of the human TCR with high affinity. As such, these proteins may be eligible for use in the treatment of oncological and autoimmune diseases defined by immunopathologies originating from TRBV9 beta-chain-bearing T cells and their use in this capacity is previously unknown in the art and does not qualify as obviously apparent to one having skill in the art.
Conclusion

APPLICANT REBUTTAL: REMARKS
Status of the Claims:
The present application contains twenty-two pending claims. Claims 1- 4, 6-9, 11, 13-16, 21 and 23 are as previously presented. Claims 10, 12, 19, 20, 22 and 24 have been amended strictly to advance prosecution. Claims 17 and 18 are cancelled without prejudice or disclaimer. Claim 5 remains as originally filed. The Applicant respectfully submits that no new matter has been added to the application by the present amendment and that full support for the claim amendments exists in the application as originally filed. No new matter has been added.
Abstract:
The Abstract has been amended to remove implied phrases and legal phraseology.
Drawings:
The description relating to Figure 3 has been amended to clarify that the measurement is of a percentage of dead cells. With respect to Figure 2, the two panels have been labelled Figure 2A and Figure 2B, as suggested by the Office. The attached replacement sheet of drawings includes these changes to Fig. 2, where the two panels are now labelled Figure 2A and Figure 2B respectfully. This sheet, which includes Figs. 2A and 2B, replaces the original sheet including Fig. 2. An annotated sheet showing the changes is also provided. The changes to the drawings are supported by the originally filed application. No new matter has been added.
Claim Objections:
Claims 10, 12, 22 and 24 have been amended to include the conjunction "or" at the end of the list. Removal of the objection is respectfully requested.
35 U.S.C. 112
The Office has rejected claims 10, 12, 19 and 20 under 35 U.S.C. 112, due to the term- "prevention of a condition." Strictly to advance prosecution, claims 22 and 24 have been amended to remove the word "prevention". Withdrawal of the rejection under 35 U.S.C. 112 is respectfully requested.
CONCLUSION

NEXT OFFICE 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
Applicant’s 26 November 2024 amendment is acknowledged. Claims 17 and 18 have been cancelled without prejudice or disclaimer. Claims 10, 12, 19, 20, 22, and 24 have been amended. Claims 1-16 and 19-24 are pending and under examination on the merit.
Rejections and Objections Withdrawn
Objections to the abstract and drawings are withdrawn with amendment to the specification by applicant.
Objections to claims 10, 12, 22, and 24 are withdrawn with amendment to the specification by applicant.
Rejection of claims 10, 12, 19 and 20 under 35 U.S.C. 112(a) for scope of enablement is withdrawn with amendment to claims by applicant. The claims now only discuss the treatment, not prevention, of a disease or disorder mediate by TRBV9-bearing T lymphocytes. As such, the enablement rejection is withdrawn.
Reasons for Allowance
The following is an examiner’s statement of reasons for allowance:
Claims 1-16 and 19-24 are allowed. Toyabe and colleagues (Clin Exp Immunol, 2003, 135(1):92-97), closest prior art, disclose a TRBV9-binding antibody/antigen-binding fragment (Fab) as well as a nucleic acid encoding the aforementioned protein. Furthermore, this group describes an expression vector, a host cell for producing the Ab/Fab after incorporation of the nucleic acid-containing vector, a method for obtaining said host cell and finally, a method for producing an antibody or an antigen-binding fragment thereof. The authors report that the disclosed antibody/antigen-binding fragment is able to bind to TRBV9 expressed on PBMCs of EBV-infected individuals.
However, the heavy chain variable and light chain variable sequences of the TRBV9-binding antibody of Toyabe is distinct from the instant claimed TRBV-9 antibody comprising a heavy chain variable and light chain variable sequences of SEQ ID NOs:16 and 18, respectively.  Further, it is not obvious to modify the antibody of Toyabe to arrive at the instant claimed antibody.  As such the aforementioned claims and their dependent claims that require the instant claimed TRBV-9 antibody comprising the amino acid sequences of SEQ ID NOs:16 and 18 are also free of prior art.
For these reasons, claims 1-16 and 19-24 are allowed.
CONCLUSION
Any comments considered necessary by applicant must be submitted no later than the
payment of the issue fee and, to avoid processing delays, should preferably accompany the issue
fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for
Allowance”.

CITED REFERENCE SUMMARIES: Ref WO1990006758: Claims:
A monoclonal antibody or derivative or fragment thereof reactive with an epitope of the constant region of the alpha chain of a T cell antigen receptor.
The antibody, derivative or fragment of claim 1 in which the T cell antigen receptor is a human T cell antigen receptor.
The antibody, derivative or fragment of claim 1 in which the epitope is contained within about amino acids
141-159 of the alpha chain.
The antibody, derivative or fragment of claim 1 in which the epitope is contained within about amino acids 212-231 of the alpha chain.
The monoclonal antibody or derivative, or fragment of claim 1 wherein the antibody has the identifying
characteristics of monoclonal antibody Î±F1, as produced by the hybridoma deposited with the ATCC and assigned
accession number HB 9900.
Monoclonal antibody Î±F1, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 9900.
The monoclonal antibody, or derivative, or
fragment of claim 1 wherein the antibody has the
identifying characteristics of monoclonal antibody Î±F1, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 9901.
Monoclonal antibody Î±F2, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 9901.
The Fv, Fab, Fab', or F(ab') 2 fragment of the monoclonal antibody of claim 1, 2, 3 or 4.
The Fv, Fab, Fab', or F(ab') 2 fragment of the monoclonal antibody of claim 6 or 8.
An antibody comprising the Fv, Fab, Fab', or F(ab') 2 fragment of the monoclonal antibody of claim 6.
An antibody comprising the Fv, Fab, Fab 7 , or F(ab') 2 fragment of the monoclonal antibody of claim 8.
A monoclonal antibody or derivative or fragment thereof reactive with an epitope of the VÎ²5.3 variable region of the beta chain of a T cell antigen receptor.
The monoclonal antibody, or derivative, or fragment of claim 13 wherein the antibody has the
identifying characteristics of monoclonal antibody W112, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 9927.
Monoclonal antibody W112, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 9927.
The Fv, Fab, Fab', or F(ab , ) 2 fragment of the monoclonal antibody of claim 13 or 15.
An antibody comprising the Fv, Fab, Fab', or F(ab') 2 fragment of the monoclonal antibody of claim 15.
A monoclonal antibody or derivative or fragment thereof reactive with an epitope of the VÎ²8.1 variable region of the beta chain of a T cell antigen receptor.
The monoclonal antibody, or derivative, or fragment of claim 18 wherein the antibody has the
identifying characteristics of monoclonal antibody 2D1, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 9928.
Monoclonal antibody 2D1, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 9928.
The Fv, Fab, Fab', or F(ab') 2 fragment of the monoclonal antibody of claim 18 or 20.
An antibody comprising the Fv, Fab, Fab', or F(ab') 2 fragment of the monoclonal antibody of claim 20.
A monoclonal antibody or derivative or fragment thereof in which the antibody is characterized by the following properties: the antibody is
(a) reactive with an epitope of the VÎ´1 variable region of the delta chain of a T cell antigen receptor; and
(b) is not of the IgG. isotype.
The monoclonal antibody of claim 23 in which the antibody is the IgG 2a isotype.
The monoclonal antibody of claim 23 in which the antibody has the identifying characteristics of monoclonal antibody 5TCS1 and which is of the IgG 2a isotype, as
produced by the hybridoma deposited with the ATCC and assigned accession number HB 10110.
The Fv, Fab, Fab', or F(ab') 2 fragment of the monoclonal antibody 'of claim 23, 24, or 25.
An antibody comprising the Fv, Fab, Fab', or
F(ab') 2 fragment of the monoclonal antibody of claim 23, 24, or 25.
A hybridoma cell line which produces the
monoclonal antibody of claim 1.
A hybridoma cell line, deposited with the ATCC and assigned accession number HB 9900, which produces monoclonal antibody Î±F1.
A hybridoma cell line deposited with the ATCC and assigned accession number HB 9901, which produces monoclonal antibody Î±F2.
monoclonal antibody of claim 13.
A hybridoma cell line, deposited with the ATCC and assigned accession number HB 9927, which produces monoclonal antibody W112.
monoclonal antibody of claim 18.
A hybridoma cell line, deposited with the ATCC and assigned accession number HB 9928, which produces monoclonal antibody 2D1.
monoclonal antibody of claim 25.
A method for diagnosing a lymphatic malignancy or other immune disorder comprising:
(a) contacting a patient's tissue with a monoclonal antibody or fragment or derivative thereof
reactive with an epitope of the constant region of the alpha chain of a T cell antigen receptor; and (b) detecting whether immunospecific binding has occurred.
The method according to claim 36, in which the tissue is contacted in vitro.
The method according to claim 36, in which the tissue is contacted in a histologic specimen.
The method according to claim 36, in which the tissue is contacted in vivo.
The monoclonal antibody or derivative or fragment of claim 36, in which the monoclonal antibody is Î±F1 or Î±F2.
A method for diagnosing a lymphatic malignancy or other immune abnormality, comprising:  (a) contacting a patient's tissue with a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the VÎ²5.3 variable region of the beta chain of a T cell antigen receptor; and
(b) detecting whether immunospecific binding has
The method of claim 41 in which the tissue is contacted in vitro.
The method of claim 41 in which the tissue is contacted in a histologic specimen.
The method of claim 41 in which the tissue is contacted in vivo.
The method of claim 41, in which the monoclonal antibody or derivative or fragment is W112.
A method for diagnosing a lymphatic malignancy or immune abnormality, comprising:
(a) contacting a patient's tissue with a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the VÎ²8 .1 variable region of the beta chain of a T cell antigen receptor; and
The method of claim 46 in which the tissue is contacted in vitro.
The method of claim 46 in which the tissue is contacted in a histologic specimen.
The method of claim 46 in which the tissue is contacted in vivo.
The method of claim 46, in which the monoclonal antibody or derivative or fragment consists of 2D1.
A method for diagnosing rheumatoid arthritis, comprising:
(a) contacting a sample obtained from a patient with a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the variable region of the beta chain of a T cell antigen receptor; and
The method according to claim 51 in which the sample is selected from the group consisting of peripheral blood, synovial tissue, and synovial fluid.
The method according to claim 51 which is performed in vitro.
The method according to claim 51 which is performed in vivo.
The method according to claim 51 in which the variable region comprises VÎ²3 .
The method according to claim 51 in which the variable region comprises VÎ²9.
The method according to claim 51 in which the variable region comprises VÎ²10.
A method for diagnosing a lymphatic malignancy or immune disorder comprising detecting the presence of nucleic acid sequences homologous to a gene encoding a variable region of an Î±Î² positive T cell antigen receptor in mRNA from a patient sample.
The method according to claim 58 in which the immune disorder is rheumatoid arthritis.
The method according to claim 59 in which the variable region of a T cell antigen receptor is a beta chain variable region.
The method according to claim 60 in which the variable region of a T cell antigen receptor is VÎ²3 .
The method according to claim 60 in which the variable region of a T cell antigen receptor is VÎ²9 .
The method according to claim 60 in which the variable region of a T cell antigen receptor is VÎ²10.
A method of increasing the number of Î³Î´ T cell receptor positive T cells with cytotoxic activity comprising exposing T lymphocytes to an effective  concentration of a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the variable region of the delta chain of a T cell antigen receptor.
The method according to claim 64 which is performed in vitro.
The method according to claim 64 which is performed in vivo.
The method according to claim 64 in which the variable region of the delta chain comprises VÎ´1.
The method according to claim 64 in which the monoclonal antibody has the binding characteristics of Î´TCS1, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 10110.
A method of decreasing the cytotoxic activity of a population of T cells comprising exposing the T cells to an effective concentration of a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the variable region of the delta chain of a T cell antigen receptor.
The method according to claim 69 which is performed in vitro.
The method according to claim 69 which is performed in vivo.
The method according to claim 69 in which the variable region of the delta chain comprises VÎ´1.
The method according to claim 69 in which the monoclonal antibody has the binding characteristics of Î´TCS1, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 10110.
A method of depleting the number of Î³Î´ positive T cells in a population of T cells comprising exposing the T cells to an effective concentration of a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the variable region of the delta chain of a T cell antigen receptor.
The method according to claim 74 which is
performed in vitro.
performed in vivo.
The method according to claim 74 in which the variable region of the delta chain comprises VÎ´1.
The method according to claim 74 in which the monoclonal antibody has the binding characteristics of Î´TCS1, as produced by the hybridoma deposited with the ATCC and assigned accession number HB 10110.
A method of treating a lymphatic malignancy or another immune abnormality comprising administering
therapeutically effective amounts of a monoclonal antibody, or fragments or derivatives thereof, which recognizes an epitope of the constant region of the alpha chain of a T cell antigen receptor, in a suitable pharmaceutical carrier, into a patient.
The method of claim 79 in which the monoclonal antibody, fragment, or derivative is linked to a
pharmacologic agent.
A method of treating a lymphatic malignancy or immune abnormality comprising administering therapeutically effective amounts of a monoclonal antibody, or fragments or derivatives thereof, which recognizes an epitope of the VÎ²5.3 variable region of the beta chain of a T cell antigen receptor, in a suitable pharmaceutical carrier, into a patient.
The method of claim 81, in which the monoclonal antibody or derivative or fragment is W112.
A method of treating a lymphatic malignancy or immune abnormality comprising administering therapeuticaly effective amounts of a monoclonal antibody, or fragments or derivatives thereof, which recognizes an epitope of the VÎ²8. 1 variable region of a T cell antigen receptor, in a suitable pharmaceutical carrier, into a patient.
The method of claim 83, in which the monoclonal antibody or fragment or derivative thereof is 2D1.
A method of treating rheumatoid arthritis
comprising administering a therapeutically effective amount of a monoclonal antibody, or fragment or derivative thereof, which recognizes an epitope of the variable region of the beta chain of a T cell antigen receptor, in a suitable phamaceutical carrier, into a patient.
The method according to claim 85 in which the variable region comprises VÎ²3 .
The method according to claim 85 in which the variable region comprises VÎ²9.
The method according to claim 85 in which the variable region comprises VÎ²10.
A method of treating a patient having a lymphatic malignancy or immune abnormality comprising administering therapeutically effective amounts of a monoclonal antibody, or fragment or derivative thereof, which recognizes an epitope of the variable region of the delta chain of a T cell antigen receptor in a suitable pharmaceutical carrier, into a patient.
The method according to claim 89, in which the variable region of the delta chain comprises VÎ´1.
The method according to claim 89, in which the monoclonal antibody, fragment, or derivative thereof has the binding characteristics of Î´TCS1, as produced by the
hybridoma deposited with the ATCC and assigned accession number HB 10110.
The method according to claim 89, in which the immune disorder is rheumatoid arthritis.
The method according to claim 89, in which the immune disorder is Felty's syndrome.
A method of treating a patient having rheumatoid arthritis comprising administering about 2 mg per day of Î´TCS1 antibody, or fragment or derivative thereof, in a suitable pharmaceutical carrier into a patient for a period of time between ten and fourteen days.
A therapeutic composition comprising effective amounts of a monoclonal antibody, or derivative or fragment thereof reactive with an epitope of the constant region of the alpha chain of a T cell antigen receptor.
A therapeutic composition comprising effective amounts of a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the V05.3 variable region of the beta chain of a T cell antigen receptor.
The composition of claim 96 in which the
monoclonal antibody or derivative or fragment thereof is W112.
A therapeutic composition comprising effective amounts of a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the VÎ²8.1 variable region of the beta chain of a T cell antigen receptor.
The composition of claim 98 in which the
monoclonal antibody is 2D1.
A therapeutic composition comprising effective amounts of a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the VÎ´1 variable region of the delta chain of a T cell antigen receptor and a pharmaceutical carrier.
The composition of claim 100 in which the monoclonal antibody or derivative or fragment has the binding characteristics of Î´TCS1, produced by the hybridoma deposited with the ATCC and assigned accession number HB 10110.
The composition of claim 100 in which the monoclonal antibody is Î´TCS1.
A therapeutic composition comprising effective amounts of a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the VÎ²3 variable region of the beta chain of a T cell antigen receptor and a pharmaceutical carrier .
A therapeutic composition comprising effective amounts of a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the VÎ²9 variable region of the beta chain of a T cell antigen receptor and a
pharmaceutical carrier.
A therapeutic composition comprising effective amounts of a monoclonal antibody or derivative or fragment thereof reactive with an epitope of the VÎ²10 variable region of the beta chain of a T cell antigen receptor and a
A method for selecting anti-T cell receptor antigen monoclonal antibodies of a particular isotype comprising:
(a) attaching antibody molecules which recognize the particular isotype to a solid support; and  (b) incubating hybridoma supernatants from hybridomas according to claims 23, 24, 25, 26, 27, 28, or 29 such that monoclonal antibodies of the particular isotype are retained by the antibodies of (a); and
(c) adding T cell lysates; and
(d) detecting whether binding of T cell antigen receptor molecules has occurred.
An antibody of any one of claims 1-8, 11-15,17-20, 22-25 which is detectably labeled.
Ref WO1994005801: Claims:
A monoclonal antibody or derivative or fragment thereof reactive with an epitope of a V/33 variable region of a T cell antigen receptor.
The monoclonal antibody of claim 1 which is reactive with an epitope of a V/33.1 variable region.
The fragment of the monoclonal antibody of claim 1, which fragment is selected from the group consisting of a Fv fragment, a Fab fragment, a Fab' fragment, and a F(ab') . fragment.
The monoclonal antibody of claim l which is not reactive with an epitope of a V/33.2 variable region of a T cell antigen receptor.
The monoclonal antibody of claim 1 which has the identifying characteristics of monoclonal antibody
5E4 as produced by a hybridoma deposited with the ATCC and assigned accession number HB 11020.
8F10 as produced by a hybridoma deposited with the ATCC and assigned accession number HB 11021.
Monoclonal antibody 5E4 as produced by a hybridoma deposited with the ATCC and assigned accession number HB 11020.
Monoclonal antibody 8F10 as produced by a hybridoma deposited with the ATCC and assigned accession number HB 11021.
S UB S TITUTESHEET
A monoclonal antibody comprising the fragment of the monoclonal antibody of claim 1, which fragment is selected from the group consisting of a Fv fragment, a Fab fragment, a Fab' fragment, and a F(ab , ) 2 fragment.
A monoclonal antibody comprising the fragment of the monoclonal antibody of claim 2, which fragment is selected from the group consisting of a Fv fragment, a Fab fragment, a Fab' fragment, and a F(ab') 2 fragment.
A monoclonal antibody comprising a fragment of the monoclonal antibody of claim 7, which fragment is selected from the group consisting of a Fv fragment, a Fab fragment, a Fab' fragment, and a F(ab') 2 fragment.
A monoclonal antibody comprising a fragment of the monoclonal antibody of claim 8, which fragment is selected from the group consisting of a Fv fragment, a Fab fragment, a Fab' fragment, and a F(ab') 2 fragment.
The monoclonal antibody of claim 1 which is humanized.
The monoclonal antibody of claim 2 which is humanized.
The monoclonal antibody of claim 5 which is humanized.
The monoclonal antibody of claim 6 which is humanized.
The monoclonal antibody of claim 1, which is detectably labeled.
The monoclonal antibody of claim 2, which is detectably labeled.
A hybridoma cell line, which produces the monoclonal antibody of claim 1.
A hybridoma cell line, which produces the monoclonal antibody of claim 2.
A hybridoma cell line, which produces the monoclonal antibody of claim 7.
A hybridoma cell line, which produces the monoclonal antibody of claim 8.
A method for diagnosing rheumatoid arthritis in a subject comprising:
(a) contacting a biological sample of a subject with a monoclonal antibody of claim 1; (b) detecting an amount of immunospecific binding that has occurred; and (c) comparing the amount of antibody bound to an amount bound in a baseline sample, in which an increase in the amount of antibody bound in the sample of the subject relative to the baseline sample is indicative of rheumatoid arthritis.
S UBSTITUTE SHEET  (a) contacting a biological sample of a subject with a fragment of the monoclonal antibody of claim 2; (b) detecting an amount of immunospecific binding that has occurred; and
(c) comparing the amount of antibody bound to an amount bound in a baseline sample, in which an increase in the amount of antibody bound in the sample of the subject relative to the baseline sample is indicative of rheumatoid arthritis.
The method of claim 23, in which the sample ntacted in vitro.
The method of claim 23, in which the sample ntacted in vivo.
The method of claim 24, in which the sample ntacted jLn vitro.
The method of claim 24, in which the sample ntacted .in vivo.
The method of claim 23, further comprising: (a) detecting expression of V/39 or V/310 in the sample of the subject; and (b) comparing the amount of V/39 or V/310 expressed with the amount expressed in the baseline sample, in which an increase in the amount in the sample of the subject relative to the baseline sample is indicative of rheumatoid arthri
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