DETAILED ACITON
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s election without traverse of Group II (drawn to a method of improving therapeutic efficacy) and the species of CD27 as biomarker in the Response filed on April 13, 2026 is acknowledged.
Claims 1-47 and 50-73 have been canceled.
Claims 74-91 have been added.
Claims 48, 49 and 74-91 are pending and currently under consideration.
3. 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.
4. Claims 48, 49 and 74-91 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.
A) Claims 48, 49 and 74-91 are indefinite in the recitation of “wherein an increase of the expression of the one or more biomarkers indicates the efficacy of a human anti-CD19 antibody in the subject”. The phrase is a relative term which renders the claim indefinite. “The increased expression of one or more biomarkers” 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.
B) Claims 48, 49 and 74-91 are indefinite in the recitation of "wherein an increase of the expression of one or more biomarkers indicates the efficacy of a huma anti-CD19 antibody in the subject" in independent claims 48 and 49. There is insufficient antecedent basis for this limitation in the claims 48 and 49.
C) Claim 76 recites the limitation "identifying step" in line1. There is insufficient antecedent basis for this limitation in the claim.
D) Claim 77 recites “wherein if the expression of one or more biomarkers is not increased then the antibody id withheld from the subject”. There is insufficient antecedent basis for this limitation in the independent claim 48 which does not recite any step of using the antibody.
E) Claims 78-80 recites “wherein the blood sample …”. There is insufficient antecedent basis for this limitation in the independent claim 48.
F) Claim 85 recites “wherein the human anti-CD19 antibody is administered subcutaneously”. There is insufficient antecedent basis in the independent claim 48 which does not recite administering anti-CD19 antibody.
G) Claims 81 and 89 recites the limitation "the Fc modification is S267E and L328F as compared to SEQ ID NO:4". There is insufficient antecedent basis for this limitation in the independent claims. Claim 81 is depended upon claim 48 and claim 89 is depended upon claim 49. Both independent claims 48 and 49 recite a human anti-CD19 antibody and not Fc modification.
In addition, claims 81 and 89 are indefinite in the recitation of having chain comprising a variable region having CDR1 comprising SEQ ID NO:13, a CDR2 comprising SEQ ID NO:14, and a CDR3 comprising SEQ ID NO:15 and “as compared to SEQ ID NO:4” because the metes and bounds of the claims are ambiguous. SEQ ID NO:4 is listed as the constant region of the antibody. Therefore, it is not clear how the CDRs can be compared to the constant region.
5. 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.
6. Claims 48, 49 and 74-91 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because the claimed invention is directed to natural phenomenon.
The claims recite an in vitro method of improving therapeutic efficacy for treatment of an autoimmune disease or an in vitro method of determining susceptibility to treatment for an autoimmune disease in a human subject in need thereof, comprising determining the expression of one or more biomarkers, wherein an increase of the expression of the one or more biomarkers indicates the efficacy of a human anti-CD19 antibody in the subject.
This judicial exception is not integrated into a practical application because the increase of the expression of one or more biomarkers is the consequence of the natural process. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the increase of the expression of the one or more biomarkders indicating the efficacy of a human anti-CD19 antibody can be performed by human using mental steps or basic critical thinking.
The Office has presented “Jan 2019 Federal Register Vol. 84, No. 4” with a two-step analysis for patent subject matter eligibility under 35 USC 101 in view of the case decisions of Supreme Court (Alice Corp Pty.Ltd v. CLS Bank Int’l (2014); Mayo Collaborative Serv. v. Prometheus Labs (2012); Association for Molecular Pathology v. Myriad Genetics Inc. (2013)) and Court of Appeals for the Federal Circuit (University of Utah Research Foundation v. Ambry Genetics Corp. (2014); PerkinElmer Inc. v. Lintema Ltd. (2012)).
The first step requires that the claimed invention ‘‘must be directed to one of the four statutory categories’’, namely process, machine, manufacture or composition, and the second step requires that the invention ‘‘must not be wholly directed to subject matter encompassing a judicially recognized exception’’, namely a law of nature, a natural phenomenon or an abstract idea (emphasis added).
The instant invention directs to an in vitro method of improving therapeutic efficacy for treatment of an autoimmune disease or an in vitro method of determining susceptibility to treatment for an autoimmune disease by measuring particular molecules, i.e. determining the expression of one or more biomarkers in the subjects and comparing the results to determine whether the subject experiences efficacy to a human anti-CD19 antibody.
Following the instructions by the guidance, the invention claimed herein satisfies the requirement of the first prong because it directs to a process (method).
With regard to the second prong Step 2A, it is to determine whether the instant invention falls within the first "judicial exception" prong, i.e. law of nature, a natural phenomenon (product of nature), or an abstract idea. The guidelines provide more detailed information concerning Abstract Ideas (groupings), including mathematical concepts, mental process (e.g. observation, evaluation, judgment, opinion), organizing human activities. If the determination shows “yes”, a second prong analysis would launch, namely whether additional elements from the claim that integrate the judicial exception into a practical application.
The key active steps in the current application include, obtaining samples, measuring target molecules in the samples, and comparing the results from the measured samples. The current invention indeed applies a “law of nature”, i.e. determining the expression of one or more biomarkers and abstract idea of comparing.
Now concerning the second prong, i.e. whether any additional elements from the claim integrates the judicial exception into a practical application, the following is noted:
Moreover, even under further Step 2B: does the claim recite additional elements that amount to significantly more than the judicial exception. The instant step of determining the expression of one or more biomarkers are well-understood, routine, conventional activity in the field and are not significant more than the judicial exception. Taken together, these steps are insignificant extra-solution activities and adds no inventive concept to the claim.
For example, Horisberger et al. (Scientific Reports. 2022, 12:9189:1-11) teach that CD21-CD27- B cells were increased in SLE patients relative to other autoimmune diseases and healthy control and CD21-CD27- B cells correlate with clinical SLE disease activity (e.g. see Abstract and pages 2-3). This indicates that CD21-CD27- B cells maybe a biomarker to assess the activity of the disease in SLE patients.
Therefore, determining the expression of one or more biomarkers such as CD27 from a subject having autoimmune disease SLE is well-understood, routine and conventional activity for those in the field of diagnostics.
Further, the step is recited at a high level of generality such that it amounts to insignificant activity, e.g., a mere gathering the expression of one or more marker step necessary to use the correlation for efficacy or determining susceptibility. Detecting whether one or more biomarkers are present in the sample from a subject having an autoimmune disease merely instructs a scientist to use any detection technique.
When recited at this high level of generality, there is no meaningful limitation, such as a particular or unconventional machine or a transformation of a particular article, in this step that distinguishes it from well understood, routine, and conventional data gathering activity engaged in by scientists prior to applicant’s invention, and at the time the application was filed, e.g., the routine and conventional techniques of detecting one or more biomarkers such as CD27 in SLE patients.
Further, it is well established that the mere physical or tangible nature of additional elements such as the obtaining and detecting steps does not automatically confer eligibility on a claim directed to an abstract idea (see, e.g., Alice Corp. v. CLS Bank Int’l, 134 S.Ct. 2347, 2358-59 (2014)).
Consideration of the additional elements, e.g. wherein the increase the expression of onr or more biomarkers indicate the efficacy of a human anti-CD19 antibody in the subject as a combination also adds no other meaningful limitations to the exception not already present when the elements are considered separately. The recited correlation is a law of nature because it is a consequence of a natural process in the body, and/or that the critical thinking step is an abstract idea similar to those found by the courts to be an exception.
Taken together act in concert to improve a technical field, the claims here do not invoke any of the considerations that courts have identified as providing significantly more than an exception. Even when viewed as a combination, the additional elements fail to transform the exception into a patent eligible application of that exception. Thus, the claim as a whole does not amount to significantly more than the exception itself (Step 2B: NO). The claims are not eligible.
Given that the instant claims merely add data gathering and well-understood, routine and conventional activities that do not impose meaningful limits on the law of nature, the claims are not eligible under 35 USC 101.
7. 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.
8. Claims 48, 49, 74-80, 82, 84-88, and 90 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims are drawn to an in vitro method of improving therapeutic efficacy for treatment of an autoimmune disease comprising determining the expression of one or more biomarkers including CD27, wherein the increase of the expression of the one or more biomarkers indicates the efficacy of a human anti-CD19 antibody in the subject. The claims do not recite the anti-CD19 antibody structure.
Dependent claims 82 and 90 recite the heavy chain amino acid sequence of SEQ ID NO:2 and amino acid substitutions S267E and L328F in the Fc region as compared to the amino acid sequence of the Fc region of SEQ ID NO:4, they do not recite the sequence of the light chain variable domain of the anti-CD19 antibody.
Dependent claims, e.g. claims 78-80, drawn to whole blood, T cells, and dendritic cells.
The specification discloses that in previous Phase 2 SLE tail results for obexelimab (interchangeable with XmAb5871 and HuAMAG7), an anti-CD19 antibody with increased FγRIIb binding affinity that suppresses B-cell activation (e.g. see [0006]).
The specification discloses laundry list of autoimmune disease including allogenic islet graft rejection (e.g. see [0068]). The specification further discloses numerous known anti-CD19 antibodies (e.g. see [0138]). In working examples, the instant specification discloses the effects of obexelimab in SLE were studied in a phase 2 double-blind randomized, placebo-controlled study. Following the administration of obexelimab, expression of individual genes and gene pathway scours were evaluated and obexelimab treatment was associated with reduction of B-cell genes and gene-sets reflective of activated B-cells and plasma cells/plasmablast (e.g. see Example 1). CD27 in B cell is a strong single gene predictor of obexelimab activity (e.g. see Example 2).
However, 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.
The scope of the claims encompasses an in vitro method of improving therapeutic efficacy for treatment or an in vitro method of determining susceptibility to treatment of any or all autoimmune disease by determining one or more biomarkers including CD27, wherein the increase of the expression of the one or more markers indicates the efficacy of any or all human anti-CD19 antibody. Further, dependent claims 78-80 further recite the expression of one or more biomarkers in whole blood sample, T cells, or dendritic cells, while the specification discloses gene expression determination of the biomarkers in B cells.
The claims do not recite the specific autoimmune disease and also do not recite sufficient structural elements for the human anti-CD19 antibody. The specification does not provide sufficient guidance and direction to identify and to enable all human anti-CD19 antibody which might show efficacy in a subject having an autoimmune disease based on the expression of ore or more biomarkers including CD27.
The specification discloses that human SLE patients were treated with anti-CD19 antibody obexelimab which is a humanized monoclonal antibody with high-affinity binding of the variable region to human CD19 and enhanced binding to FcγRIIb with 225-fold increase over IgG1 (e.g. see Merrill et al. Arthritis & Rheumatology 2023, 75;12:2185-2194, especially 2nd full paragraph in left col. in page 2186).
Horton et al. (The Journal of Immunology, 2011 186:4223-4233) teach that anti-CD19 antibody XmAb5871 (obexelimab) coengages FcγRIIb with B cell receptor complex (CD19), stimulates phosphorylation of the inhibitory pathway ITIM of FcγRIIb and spuppressed BCR-induced calcium mobilization, proliferation and costimulatory molecule expression of human B cells from healthy volunteers and SLE patients (e.g. see Abstract). Horton et al. further teach that the inhibitory activity required coengagement of both FcγRIIb and CD19 by Fc and Fv domains, respectively on the same antibody as opposed to simultaneous engagement by different antibodies, because the combination of isotype control and Fc control antibodies was ineffective in coengagement of FcγRIIb and BCR complexes (e.g. see page 4225).
Therefore, the disclosure of specific known anti-CD19 antibody obexelimab (XmAb5871) in the specification is not sufficient to enable the entire genus of a human anti-CD19 antibody recited in the instant claims. The claims do not recite sufficient structural elements including Fv and Fc that contains mutations with enhanced FcγRIIb binding for the human anti-CD19 antibody encompassed by the claimed methods.
Regarding biomarkers in autoimmune disease, Horisberger et al. (Scientific Reports 2022, 12;9189:1-11) teach that determining disease activity in SLE patients is crucial to refine therapy. However, given the heterogeneity of SLE and the lack of consistent biomarkers, monitoring disease activity is challenging and identifying reliable widely available biomarkers remain unmet need (e.g. see 1st paragraph in page 1). Horisberger et al. further teach that CD21-CD27- B cells were increased in SLE patients relative to other autoimmune diseases and healthy control and CD21-CD27- B cells correlate with clinical SLE disease activity (e.g. see Abstract and pages 2-3). This indicates that CD21-CD27- B cells maybe a biomarker to assess the activity of the disease in SLE patients but are not suitable markers for other autoimmune diseases.
The instant specification discloses only one human IgG4 anti-CD19 antibody consisting amino acid substitutions S267E and L328F treating SLE patient, and an invitro method of determining susceptibility to treatment for SLE in a human subject administered a human anti-CD19 antibody by determining the expression of one or more biomarkers as recited in claim 48. The human anti-CD19 antibody comprises light chain comprising CDRs1-3 of SEQ ID NO:10, 11, and 12, respectively, heavy chain CDRs: 1-3 of SEQ ID NOs: 13, 14, and 15, respectively, and an Fc region comprising SEQ ID NO:4 consisting amino acid substitutions S267E and L328F.
The claims recite an in vitro method of improving therapeutic efficacy for treatment of an autoimmune disease or in vitro method of determining susceptibility to treatment for an autoimmune disease, by determining the expression of one or more biomarkers including CD27, and wherein the increase expression of the one or more biomarker indicates efficacy of the anti-CD19 antibody treatment. The claims are not limited to a particular anti-CD19 antibody, nor do they limit the autoimmune diseases.
There is insufficient objective evidence that the specific structurally defined anti-CD19 antibody consisting specific amino acid substitutions S267E and L328F treating SLE patients as disclosed in the specification as-filed can be extrapolated to predict the efficacy of all anti-CD19 antibody in treating all autoimmune diseases.
The scope of the required enablement varies inversely with the degree of predictability involved and in cases involving unpredictable factors such as physiological activity more may be required. See MPEP 2164.03 and 2164.02.
Given the relatively incomplete understanding in the biotechnological field involved and the lack of a reasonable correlation between the narrow disclosure in the specification and broad scope of protection sought in the claims; the lack of enablement is deemed appropriate. See MPEP 2164.08.
In view of the lack of predictability of the art to which the invention pertains, the in vitro method of improving therapeutic efficacy for treatment of an autoimmune disease or in vitro method of determining susceptibility to treatment for an autoimmune disease by determining the expression of one or more biomarker including CD27, in whole blood, T cell, or dendritic cell, and use it to predict the efficacy of the genus of a human anti-CD19 antibody in the subject would be unpredictable and the experimentation left to those skilled in the art is unnecessarily, and improperly, extensive and undue.
9. No claim is allowed.
10. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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