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 .
Election/Restrictions
Applicants’ election without traverse of the invention of Group 1 (claims directed to methods comprising detecting cells) in the reply filed on 01/05/2026 is acknowledged.
Applicants’ additional elections related to the election of species requirements (as set forth in the Requirement of 11/10/2025) are acknowledges. In light of the Examiner’s search and analysis of the claimed subject matter, the species election requirements are withdrawn.
Claim 25 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 01/05/2026.
Claim Rejections - 35 USC § 112 - Indefiniteness
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 1, 2, 5-7, 10, 11, and 13-24 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.
Claims 1, 2, 5-7, 10, 11, and 13-24 are unclear over the stated purpose of the claims as “determining the presence of EBV-driven pathogenic B cells”, as recited in the preamble of claim 1, because the relevant step in claim 1 recites “detecting … EBV-infected B cells” and it is not clear whether or not “EBV-infected B cells” are the same as the “EBV-driven pathogenic B cells” of the preamble. Where EBV-infected cells may not be pathogenic, it is unclear how their detection meets the requirement of “determining the presence of EBV-driven pathogenic B cells” as recited in the preamble of claim 1.
Claims 1, 2, 5-7, 10, 11, and 13-24 are unclear over recitation the combination of limitations that is “detecting … EBV-infected B cells” and “if EBV-infected B cells are detected treating said patient”. The claims are unclear over the required steps of the claims because the first limitation of “detecting … EBV-infected B cells” appears to require a positive process step that results in the detection of the EBV-infected B cells. But in the second limitation, the recitation of the term “if” appears to indicate that the EBV-infected B cells may not be detected.
Claims 1, 2, 5-7, 10, 11, and 13-24 are unclear over recitation of the limitation “treating said patient” because there is no antecedent basis for any “patient”.
Claim 2 is unclear over recitation of the phrase “the individual suffers from an autoimmune disease, optionally multiple sclerosis, …” because it is unclear if the recited pathologies are intended to be a required element that limits the autoimmune disease of the claim.
Claim 11 is unclear over recitation of the limitation “detection of the markers associated with active EBV infection is used to monitor treatment response and guide additional treatment”, because the claim does not set forth any steps or requirements for the claimed use. It is unclear what steps or procedures are added to the methods of claim 7, from which claim 11 depends, to arrive at a method in which the detection is “used to monitor treatment response and guide additional treatment”.
Claims 19 and 20 are unclear over recitation of the limitation “the treatment comprises inhibition of pathogenic B cell”, as recited in claim 19. The claims depend form claim 13, and claim 13 depends from claim 1. Claim 1 recites, in the alternative, treatments for a patient as “an EBV-infected B cell depleting or inhibiting therapeutic”, and claim 13 sets forth that “the treatment comprises depletion”. The instantly rejected claims are unclear because claim 19 sets forth “the treatment comprises inhibition”, but it is unclear if the methods of claim 19 are intended to set forth that the treatment of claim 19 is the same treatment as required for claim 13 and that the treatment has two functions (i.e.: depleting (as required by claim 13) and inhibiting (as required by claim 19)), or if the rejected claims require that an additional different treatment is provided.
Claim 22 is unclear over recitation of the limitation “the agent is an altered peptide ligand”. In the recitation that the peptide ligand of the claim is “altered”, the term “altered” is a relative term which renders the claim indefinite. The term “altered” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is not clear what standard is used to determine that any peptide ligand is “altered”.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 5, 6, 7, 10, 11 rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions to patentability, which are abstract ideas and natural phenomena, without significantly more.
The claim(s) recite(s) “glialcam epitope is cross-reactive with an EBNA-1 epitope present in the EBV infected B cells” (recited in claim 5 from which claim 6 depends). The polypeptide sequence elements of the glialcam (i.e.: glial cell adhesion molecule, also known as HepaCAM) protein and the EBNA-1 (i.e.: Epstein-Barr virus nuclear antigen 1) protein which are similar in structure are naturally occurring parts of those biological molecules, and so the limitation that they have cross-reactivity is a natural phenomenon (i.e.: an antibody or immune receptor, raised against a specific pathogen or substance, binds to a different but structurally similar antigen) (MPEP 2106.04(b)I). The claims also recite detecting EBV-driven pathogenic B cells “determining the presence of markers associated with active EBV infection in the B cells”. This association is a part of the natural gene expression of a cell (i.e.: EBV infected cells express specific gene products), and thus the limitation is directed to a natural phenomenon. Additionally, where the limitation is directed to the analysis of data to reach a conclusion (e.g.: detection of a marker provides an indication that a particular cell is present), such a mental evaluation of data is an abstract idea (MPEP 2106.04(a)(2)III). Similarly, where the claims recite that the detection of a marker “is used to monitor treatment response and guide additional treatment” (claims 11), such a recitation is the evaluation of data to establish a judgment, and is an abstract idea.
This judicial exception is not integrated into a practical application because the claims do not require any practical steps related to the identified judicial exceptions. It is noted that claim 1 recites “treating said patient with an EBV-infected B cell depleting or inhibiting therapeutic” but the treatment limitation is included as a conditional clause with the phrase “if EBV-infected B cells are detected” (which has been addressed under 35 USC 112(b) earlier in this Office Action. In the instant case the claims appear to encompass embodiments in which the claimed methods end with the judicial exception(s).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the rejected claims depend form claim 1, and thus the additional elements are the steps of detecting EBV-infected B cells in a sample, and treating with a if EBV-infected B cells are detected treating said patient with an EBV-infected B cell depleting or inhibiting therapeutic. But these additional elements are routine and conventional when considering the teachings of the related prior art. For example, Cavalcante et al (2017) teaches methods that include the detection of EBV-infected B cells in a sample, and treatment of a subject with azathioprine which is a treatment that reduces B cell numbers and function by inhibiting purine synthesis, essential for DNA/RNA production in rapidly dividing lymphocytes (e.g.: Table 1; Fig 4).
Claim Rejections - 35 USC § 102
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.
Claim(s) 1, 2, 5, 6, 7, 10, 11, 13 and19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Cavalcante et al (2017).
Relevant to the methods of the rejected claims, reference teaches the analysis of samples from subject with myasthenia gravis (e.g: Abstract; relevant to claim 2) that includes the detection of EBV-infected B-cells using the detection of LMP2 protein (e.g.: MG (+) T24 samples in Figure 4; relevant to claims 1, 7 and 10) in a sample, and treating the subject with azathioprine (e.g.: MG (+) T24 subject in Table 1) which is a treatment that reduces B cell numbers and function by inhibiting purine synthesis, essential for DNA/RNA production in rapidly dividing lymphocytes (relevant to claims 1, 13 and 19).
Relevant to claims 5 and 6, the claims, the cross reactivity between glialcam and EBNA-1 in EBV infected cells is an inherent property of the sequences of the proteins.
Relevant to claim 11, the claim does not add any additional practical steps to the methods of claim 1, and as such the teachings of the prior art with regard to claim 1, where markers are detected in treated subjects, are considered to be anticipatory of the methods of claim 11.
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.
Claim(s) 1, 2, 5, 6, 7, 10, 11, 13 and 19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sheahan (2017) in view of Pender (2003).
Relevant to the limitations of claim 1, Sheahan teaches that Epstein-Barr virus as a risk factor for MS (e.g.: p. 13; relevant to claim 2), that EBV infects B lymphocytes (e.g.: p.16), and demonstrates the detection of EBV infected B-cells (e.g.: p.40; p.45). Further relevant to claim 1, Sheahan teaches that B lymphocyte depletion is a therapy for MS (e.g.: p.8), and suggests (e.g.: p.88-90) that B lymphocyte depletion could be improved with specific targeting of particular EBV-infected B lymphocyte subset populations (relevant to claim 13 and 19).
Relevant to the rejection of claims 7 and 10, Sheahan exemplifies the detection of Epstein-Barr virus-encoded small RNAs (EBER) (e.g.: p.43), and further teaches that Latent Membrane Protein 1 and 2 (LMP1 and LMP2) are EBV proteins express in latency that aid in the persistence of the virus within B lymphocytes (e.g.: p.19).
Pender et al provides similar teachings related to EBV infection persistence in B lymphocytes associated with different autoimmune diseases (e.g.: p.584 - Universally high prevalence of EBV seropositivity in MS and SLE; p.584 - Defective T-cell control of EBV-infected B cells in different chronic autoimmune diseases). Pender further suggests that progression of autoimmune diseases associated with EBV-infected B cells could be inhibited by control of EBV-infected B cells, achieved by: general B-cell depletion (e.g. by rituximab); EBV-specific cytotoxic CD8+ T cells; or inhibition of EBV-infected B cells with antiviral agents or agents that interfere with the anti-apoptotic effects of viral latent membrane proteins.
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have treated an EBV-infected-B-cell-related autoimmune disease in a subject with a treatment that depletes or inhibits EBV-infected B-cells after the detection of EBV-infected B-cells in a sample from the subject. The skilled artisan would have been motivated to detect EBV-infected B-cells in a sample from a subject based on the teachings of both Sheahan and Pender that EBV infection of B cells is related to autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. The skilled artisan would be motivated to apply treatments that deplete or inhibit EBV-infected B cells based on the suggestions of both Sheahan and Pender that such treatments may address a cause of autoimmune pathology (i.e.: EBV-infected B cells). With regard to the limitations of claim 11, where the prior art teaches that EBV-infected B cells are associated with the presence of autoimmune disease and may be a target for therapeutic treatment, and that EBV-infected B cells have detectable markers associated with EBV infection, it would have been obvious to have used such markers to monitor treatment because the skilled artisan would recognize that the amount or levels of the marker would provide an indication of the depletion of the EBV-infected B cells.
Relevant to claims 5 and 6, the claims, the cross reactivity between glialcam and EBNA-1 in EBV infected cells is an inherent property of the sequences of the proteins.
Claim(s) 15 and 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sheahan (2017) in view of Pender (2003), as applied to claims 1, 2, 5, 6, 7, 10, 11, 13 and 19, and further in view of Bollard et al (2014).
Sheahan in view of Pender renders obvious methods of detecting EBV-infected cells in a sample from a subject, and treating the subject with an EBV-infected cell depleting or inhibiting therapeutic that depletes pathogenic B cells. Further relevant to the instantly rejected claims, Pender suggests treatments including EBV-specific cytotoxic CD8+ T cells.
Sheahan in view of Pender does not specifically teach an agent targeted to markers present on B cells actively infected with EBV (claim 14), where the markers are LMP1 or LMP2 (claims 16), but such treatments related to EBV-related pathology were known in the prior art and are taught by Bollard et al.
Bollard et al teaches the expansion of cytotoxic T lymphocytes (CTLs) directed to the LMP2 or LMP1 EBV protein (e.g.: p.799 - Generation of LMP-Specific CTLs) and the use of the cells as a therapeutic to alleviate pathology related to EBV-infection (e.g.: Fig. 2).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have administered the therapeutic CTLs of Bollard et al to deplete or inhibit EBV-infected B-cells (as suggested by Sheahan and Pender) in a patient with an autoimmune disease in which EBV-infected cells had been detected (as suggested by Sheahan and Pender). The skilled artisan would have had a reasonable expectation of success based on the expressed teachings of Bollard et al that CTLs directed to the LMP2 or LMP1 EBV protein are an effective treatment of EBV-infection related pathology.
Claim(s) 14, 17 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sheahan (2017) in view of Pender (2003) and Bollard et al (2014), as applied to claims 15 and 16, and further in view of Liebowitz et al (1987) and Ducry et al (2010).
Sheahan in view of Pender and Bollard et al renders obvious methods of detecting EBV-infected cells in a sample from a subject, and treating the subject with an EBV-infected cell depleting or inhibiting therapeutic that depletes pathogenic B cells by targeting EBV LMP2 or LMP1 proteins.
Sheahan in view of Pender and Bollard et al does not teach therapeutics that are monoclonal antibodies (claim 14) or are antibodies (claim 17) complexed with a cytotoxic agent (claim 18).
But monoclonal antibodies directed to EBV proteins were known in the prior art, and the development of therapeutic antibodies complexed with cytotoxic agents was also known in the art.
Liebowitz et al teaches the use of a monoclonal antibody, termed S12, which has specificity to the Epstein-Barr virus (EBV) latent infection membrane protein (LMP) (e.g.: Fig.1 shows the LMP1 sequence).
Ducry et al teaches that monoclonal antibodies are an approach to achieve selective treatment, and that antibody-drug conjugates including monoclonal antibodies (mAbs) linked to cell-killing drugs offer high binding specificity for target-specific antigens that can be used as vehicles to target cell-killing payloads to target cells (e.g.: Figure 1; p.5).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have used a monoclonal antibody directed to LMP1 (as taught by Liebowitz et al) conjugated to a cytotoxic agent (as taught by Ducry et al) as a therapeutic in the methods rendered obvious by Sheahan in view of Pender and Bollard et al. this skilled artisan would have been motivated to use a monoclonal antibody directed to LMP1 and conjugated to a cytotoxic agent based on the expressed teachings of Sheahan and Pender that that such treatments directed to EBV-infected B cells may address a cause of autoimmune pathology, and the expressed teachings of Liebowitz et al that the S12 monoclonal antibody has specificity for the LMP protein that is expressed by EBV infected cells and the expressed teachings of Ducry et al that conjugating a cytotoxic component to a monoclonal antibody provides a specific method to kill target cells.
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sheahan (2017) in view of Pender (2003), as applied to claims 1, 2, 5, 6, 7, 10, 11, 13 and 19, and further in view of Ye et al (2019).
Sheahan in view of Pender renders obvious methods of detecting EBV-infected cells in a sample from a subject, and treating the subject with an EBV-infected cell depleting or inhibiting therapeutic that depletes pathogenic B cells.
Sheahan in view of Pender does not specifically teach treating cells with a BTK inhibitor, but such treatments related to EBV-related pathology were known in the prior art and are taught by Ye et al.
Ye et al teaches that Bruton's tyrosine kinase (Btk) participates in EBV-related pathology, and teaches that therapeutic regimens including the BTK inhibitor (ibrutinib) are used in the treatment of EBV related pathology (e.g.: p.1284 (e.g.: p.6525 - Effect of Btk in viral infections; Table 1).
It would have been prima facie obvious to someone with ordinary skill in the relevant art before the effective filing date of the rejected claims to have administered the therapeutic BTK inhibitor ibrutinib (as taught by Ye et al) to inhibit EBV-infected B-cells (as suggested by Sheahan and Pender) in a patient with an autoimmune disease in which EBV-infected cells had been detected (as suggested by Sheahan and Pender). The skilled artisan would have had a reasonable expectation of success based on the expressed teachings of Ye et al that therapeutic regimens including BTK inhibitors are an effective treatment of EBV-infection related pathology.
Claim Rejections - 35 USC § 112 – Written Description
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 21-24 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.
MPEP § 2163 lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the Application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed, and correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. “Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient.”
The U.S. Court of Appeals for the Federal Circuit recently reaffirmed, in an en banc decision, that the written description requirement for a genus may be satisfied either by (i) the disclosure of a representative number of species falling within the scope of the genus or (ii) structural features common to the members of the genus so that one of skill in the art can "visualize or recognize" the members of the genus. Ariad Pharmaceuticals', Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350, 94 U.S.P.Q.2d 1161, 1171 (en banc) (Fed. Cir. 2010), citing Regents" of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 1568-69, 43 U.S.P.Q.2d 1398, 1406 (Fed. Cir. 1997) and AbbVie v. Janssen Biotech and Centocor Biologics (Fed. Cir. 2014).
The rejected claims are directed to methods of treatment that deplete pathogenic EBV-infected B-cells, where the treatment comprises administration of an agent to tolerize immune cells to a cross reactive EBNA-1/glialcam epitope. Here it is noted that while the specification asserts that plasma of MS patients contains antibodies that are cross reactive to EBNA-1 and glialcam (e.g.: specification at page 42), there is no disclosure of any methods in which a subject is tolerized to any antigen or epitope that is shared between EBNA-1 and glialcam. There is no exemplification that such a tolerization in fact will deplete EBV-infected B-cells and alleviate any pathological symptoms.
Additionally, where the related art teaches the difficult in effectively tolerizing any subject to a particular epitope, the mere idea of a method of treating by tolerizing immune cells is insufficient for a written description of the methods of the rejected claims. A showing of an epitope that is shared among proteins is not a description of methods of treatment by tolerizing immune cells to the epitope. The disclosure a cross reactivity does demonstrate possession of a methods of treatment. Huffaker et al (2021) teaches that tolerogenic therapies that focus on boosting regulatory immune responses face daunting hurdles in the form of established immunological memory and robust redundant effector activation pathways, involving both adaptive and innate immunity. And Nepom et al (2012) teaches that while any identified protein may be a biomarker of a pathology, biomarkers may not be causally related to a disease but may simply reflect an association. Nepom et al further discusses technical difficulties, providing: immune tolerance in clinical medicine is a daunting challenge, with complexities of multiple interacting immunological mechanisms overlaid on a background of variation in patterns of disease.
Considering the limited teachings of the application as filed, and the complexities understood in the related art, it is the conclusion that the application as filed does not provide an adequate description of the methods of the rejected claims.
Conclusion
No claim is allowed
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. Zhu et al (2020) teaches an EBV LMP-2-affibody conjugated to affitoxin for targeted therapy of nasopharyngeal carcinoma related to EBV infection.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
Prosecution Insights