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 .
Election/Restriction
The response filed on 04/27/26 to the restriction requirement of 02/25/26 has been received. Without traverse, Applicant has elected to prosecute the invention of Group I (claims 8-9). Further, as the species, Applicant has elected memory B cells of at least 70% which are indicative of early efficacy of cladribine treatment. Applicant has by way of this amendment, added claim 22. Claims 10-21 stand withdrawn as being directed to a non-elected invention.
Status of Claims
Claims 8-22 are pending.
Claims 10-21 are withdrawn from further consideration by the examiner under 37 CFR 1.142(b) as being drawn to a non-elected invention.
Claim 22 is new.
Claims 8, 9 and 22 are currently under examination on the merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The U.S. effective filing date of all claims under examination is set at 03/03/2021 based on the provisional application 63/156,196 (filed 03/03/2021).
Information Disclosure Statement
The information disclosure statements (IDS) are being considered by the examiner.
Drawings
The drawings are objected to because:
Figure 4: It is difficult to differentiate between the different “colors” of the plotted data lines for the different types of B cells and T cells presented in the graphs. It is suggested that each type of B or T cells are to be presented with different shapes in the graphs;
Figure 5: It is difficult to differentiate between the different “colors” of the plotted data lines for the different types of NK cells presented in the graphs. It is suggested that each type of NK cell be presented with different shapes in the graphs;
Figure 6: It is difficult to differentiate between the different “colors” of the plotted data lines for IgG and IgM presented in the graph. It is suggested that IgG and IgM be presented with different shapes in the graph;
Figures 8-10: The figure legends on Pg 63 of specification for Figures 8 to 10 indicate that the colors have been used to describe the figures. The figures presented are in black and white and so make it difficult to differentiate the color intensity that is shown and also the blue and red that display the positive and negative correlations respectively;
Drawing Pg 11 and 12: The Figure on Pg 11 of the submitted Drawings is missing its figure label (this appears to be Figure 11) and accordingly the figure on Pg 12 of Drawings should be labeled with "continuation Figure 11";
Figures 11-13: These figures appear to be missing x-axis labels; and
Drawing Pg 14 and 15: The Figure on Pg 14 of the submitted Drawings is missing its figure label (this appears to be Figure 13) and accordingly the figure on Pg 15 of Drawings should be labeled with "continuation Figure 13".
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.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable codes:
www.mdpi (on Pg 59);
www.frontiersin.org (on Pg 59);
https://doi.org/10.1155/2020/7523914 (Pg. 60);
www.mdpi.com/journal/jpm (on Pg. 60);
www. nature. com/naturecommunications (on Pg. 62); and
https://doi.org/10.1007/s13317-018-0109-x (on Pg. 62).
Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 8 is objected to because of the following informalities:
Claim 8 appears to have several typographical errors as described below:
the term “Plasmacells” after CD38+ should be “plasma cells” (line 22 of claim 8 on Pg 2);
the capital letter of “s” in the term “Short lived” should be lowercase “s” to recite “short lived” (line 23 of claim 8 on Pg 2);
the term “plasmacells” should be “plasma cells” (line 23 of claim 8 on Pg 2);
the term “Tnaive cells” should be “T naïve cells” (line 21 of claim 8 on Pg 3);
the term “CD4 + Central memory T cells” should be “CD4+ central memory T cells”, where the space between “CD4” and “+” should be deleted and the uppercase “C” for “Central” should be a lowercase “c” (line 20 of claim 8 on Pg 3); and
the term “Effector Memory T cells” should be “effector memory T cells” where the uppercase “E” and “M” should be recited in lowercase “e” and “m” (line 21 of claim 8 on Pg 3).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 8, 9 and 22 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AlA), 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-AlA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 8, 9 and 22 are rejected because claim 8 does not recite a conjunction between clause a), b) and c). Therefore, the metes-and-bounds are unclear as to whether all three of clause a) through c), or whether just one of clause a), b) or c), are required to be practiced for the method to predict response of a patient treated with cladribine for treatment of a disorder. The Examiner has interpreted the claims to require only one of clause a), b) or c) as the limitation of the method claims.
Claims 8, 9 and 22 are rejected because claim 8 does not recite conjunctions in the following clauses or limitations:
between lines 18 and 19 on Pg 2 as shown below;
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between lines 14 and 15 on Pg 3 as shown below; and
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between lines 7 and 8 on Pg 4 as shown below;
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The Examiner has interpreted the claims to require both steps as shown in (a), (b) and (c) above as required limitations of the method claims.
Claims 8, 9 and 22 are rejected because claim 8 recites the following phrases:-
“A method to predict the response of a patient" (line 1 of Pg 2); there is insufficient antecedent basis for “the response” in the claim;
“for the treatment of" (line 2 of Pg 2); there is insufficient antecedent basis for the limitation “the treatment" in the claim;
“before the start of treatment” (line 15 of Pg 2); “before the start of treatment” (line 11 of Pg 3); and “before the start of treatment” (line 4 of Pg 4); there is insufficient antecedent basis for “the start of treatment” in the claim;
“the baseline levels” (line 19 of Pg 2); “the baseline levels” (line 15 of Pg 3); and “the baseline levels” (line 8 of Pg 4); there is insufficient antecedent basis for “the baseline levels” in the claim;
“the Treg/Teff cell ratio” (line 22 of Pg 3); there is insufficient antecedent basis for “the Treg/Teff cell ratio” in the claim;
“the Breg/B memory cell ratio” (line 24 of Pg 3); there is insufficient antecedent basis for “the Breg/B memory cell ratio” in the claim;
“the NKreg/NK eff cell ratio” (line 26 of Pg 3); there is insufficient antecedent basis for “the NKreg/NK eff cell ratio” in the claim.
Claims 8, 9 and 22 are rejected because claim 8 recites the phrases “said deviations are given as decrease from the baseline levels” in steps a), b) and c) of claim 8, but without clearly describing what the baseline levels are in reference to. The metes-and-bounds are unclear because the baseline levels have not been clearly defined.
Claim Rejections 35 U.S.C.112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 8 and 22 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 a method to predict response of a patient treated with cladribine for treatment of multiple sclerosis based on deviations of cell populations as recited in the claims, does not reasonably provide enablement for a method to predict response of a patient treated with cladribine for treatment of just any autoimmune disorder based on deviations of cell populations as recited in the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to perform the invention commensurate in scope with these claims.
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.
The nature of the invention
Claim 8 and 22 are drawn to a method to predict response of a patient treated with cladribine for treatment of an autoimmune disorder where multiple sclerosis is an example of. However, the claims include all types of autoimmune disorders which is a diverse and large list that in practice include more than 80 clinically distinct diseases (Karopka et al. BMC Bioinformatics 7, 325 (2006), 1-17; see Abstract ).
The breadth of the claims
The claims are broad in that it encompasses predicting response of a patient treated with cladribine for treatment of every possible type of autoimmune disorders where there are numerous distinct types.
The amount of direction provided by the inventor/the existence of working examples
The specification at most discloses only one autoimmune disorder which is multiple sclerosis as the disorder that is treated by cladribine. The specification on Pg 1 discloses under “Brief summary of the invention” that multiple sclerosis (MS) is characterized by the presence of focal and diffuse inflammatory and degenerative lesions in the CNS. The specification discloses in Example 1 (Pg 64-78), the characterization of peripheral immune cell dynamics and repopulation patterns after treatment with cladribine tablets in the MAGNIFY-MS study where patients are aged 18 and above, having highly active relapsing MS were enrolled in the study to receive cladribine tablets 3.5 mg/kg cumulative dose over 2 years, and where analysis involved longitudinal evaluation of peripheral blood immune cell subtypes (see Table 1).
The disclosure does not discuss, or demonstrate through working examples, any other autoimmune disorder that is treated by cladribine and wherein predicting the response of a patient treated with cladribine was disclosed.
The state of the art/the level of predictability in the art
The state of the art teaches that cladribine is approved for the treatment of adults with active multiple sclerosis (Siddiqui et al. Current Medical Research and Opinion, 34(8), 1361–1371; 2018. See Pg 1361 column right spanning paragraph to Pg 1362 column left spanning paragraph) and have been studied in clinical trials for acute myeloid leukemia in pediatric as well as adult patients (Molica et al. Leukemia & Lymphoma, 61(3), 536–545; 2020. See Abstract and Tables 1 and 2).
Not knowing and absent further experimentation, which autoimmune disorders can be treated with cladribine, leads to one having no predictability or expectation of success for a method to predict a response of a patient treated with cladribine for treatment of any autoimmune disorder. Such random experimentation to identify at a later time which autoimmune disorder is able or is not able to be treated by cladribine such that the treated patient would have a response that could be predicted as embraced by Applicant’s claims is undue experimentation.
Conclusion
In view of the Wands factors as discussed above, one of ordinary skill in the art would have to engage in undue experimentation to practice the full scope of the instant claimed invention. This is because the art teaches that a patient with multiple sclerosis treated with cladribine are responsive to said treatment and as such a method to predict the response of said patient treated with cladribine for treatment of multiple sclerosis would be not be unpredictable while a patient with an autoimmune disorder that is not multiple sclerosis would be unpredictable, and the specification does not provide direction on which autoimmune disorder can be treated with cladribine and where a method to predict response after said treatment can be performed for the method as claimed. In other words, the specification does nothing to ameliorate these concerns over the breadth of the claims rejected above with respect to an autoimmune disorder that is not multiple sclerosis, therefore, one would be burdened with undue experimentation to perform the method of instant claims as broadly as they are currently claimed.
Enablement can be met by amending claim 8 to recite multiple sclerosis as the disorder. Of note, if claim 8 were amended as suggested, then claim 9 would not be further limiting claim 8.
Claim Rejections - 35 USC § 101 (First)
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 8 and 9 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 claims do not recite a process, machine, manufacture, or composition of matter. The claims do not fall within at least one of the four categories of patent eligible subject matter because “predicting response of a patient treated with cladribine…..wherein cell populations are determined in one or more body fluids samples at different stages of cladribine treatment” is not a process, machine, manufacture, or composition of matter. See MPEP 2106.03. The claims are not drawn to a “process”/method because the claims are not drawn to an act or step, a series of acts or steps, a mode of treatment of certain materials to produce a given result, or an act, or a series of acts, performed upon subject-matter to be transformed and reduced to a different state or thing. Note steps are recited in ‘passive’ voice and do not require one performing the claimed method to actively detect cell populations. The claims are not drawn to a “machine” because claims are not drawn to a concrete thing, consisting of parts, or of certain devices and combination of devices. The claims are not drawn to a “manufacture” because the claims are not drawn to a tangible article. The claims are not drawn to a “composition of matter” because the claims are not drawn to a combination of two or more substances.
Claim Rejections - 35 USC § 101 (Second)
Claims 8, 9 and 22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. The rationale for this determination is explained below:
Claims 8, 9, and 22 are directed to natural phenomenon because the claims recite natural phenomenon (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: cell populations correlating with treatment response. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations of claim 8 passively stating cell populations in body fluids “are determined” in samples upon administration of cladribine treatment and claim 22 stating cell populations are quantified by contacting cells with a fluorophore-conjugated antibody for a biomarker on the cells (“Step 2B”). Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance).
MPEP 2106.05(d)(II) provides a non-limiting list of laboratory techniques recognized by courts as well-understood, routine, conventional activity. These techniques include:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017).
Quantifying cell populations by contacting cells with a fluorophore-conjugated antibody for a biomarker on the cells is conventional and routine in the art (see Pg 2203 column right, Section titled “B-cell subsets” of Moser et al. (Ann. Clin. Transl. Neurol., 7: 2199-2212; 2020), for example). Further, the specification acknowledges that methods to identify and number immune cells or populations of immune cells are “well known in the art” as phenotyping or immunophenotyping, and are typically based on flux cytometry, FACs or FACs analysis (Pg 8 line 6-8) and use fluorophore-conjugated antibodies (Pg 8 line 10-11). Here, the claims do not contain any significant additional elements or steps beyond the observation of judicial exception(s) present when performing routine and conventional methods. Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the judicial exception(s). Further, just as methods comprising detecting paternal DNA sequences in particular samples by PCR was identified in Ariosa v. Sequenom as "well-known, routine, and conventional" (see first paragraph on page 13 of Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015)) even though the prior art did not demonstrate detecting said paternal DNA sequences in said particular samples by PCR, the methods of contacting cell populations with fluorophore-conjugated antibody encompassed by the instant claims are well-known, routine, and conventional. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (common methods of detecting cell population changes in body fluids) are routinely performed in the art to obtain data regarding cell populations. Moreover, “[w]hile preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility…." Ariosa Diagnostics, Inc., v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015), cert. denied, No. 15-1182, 2016 WL 1117246 (U.S. June 27, 2016). Further, “Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2117 (2013). The claims do not recite something “significantly more” than the judicial exception(s); rather, the claims “simply inform” the natural phenomenon to one performing routine active method steps and do not amount to significantly more than the judicial exception(s).
Claim Rejections - 35 USC § 102 and 35 USC § 103
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claims 8, 9 and 22 are rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Moser et al. (Ann. Clin. Transl. Neurol., 7: 2199-2212; 2020).
Moser et al. teaches long-term peripheral immune cell profiling reveals further targets of oral cladribine in MS (Title). They teach that cladribine (CLAD) is a pulsed immune reconstitution therapy approved for active multiple sclerosis (MS) and that short-term immunological effects of cladribine on peripheral immune cell subsets have previously been known (Abstract “Objectives”). They also teach studies on immune cells isolated from the peripheral blood of patients with MS (pwMS) before treatment of CLAD tablets and every three months thereafter over the course of 2 years by flow cytometric analysis (Pg 2200 column left, first full paragraph lines 15-22).
Moser et al. also teach that there is selectivity of CLAD towards central memory T cells and memory B cells and that hyper-repopulation of maturing B cells was detected after CLAD treatment (Abstract “Results” and Figures 2 and 3). They further teach that: (i) counts of classical (−65%) and various nonclassical TH17 cells (−84% to −87%) were markedly reduced 24 months after treatment start, and were comparable with depletion rates of class-switched memory B-cell phenotypes (−87% to −95%) (Abstract and Figure 2); (ii) the nadir of TH cells was more pronounced in the second treatment year (Abstract and Figure 5); (iii) an expansion of regulatory T, B and NK cells was observed (Abstract and Figure 4); and (iv) natural killer T cells (NKT) were only depleted in year two and did not recover (Abstract and Figure 1).
Moser et al. further teach that immune cell phenotyping was performed by fluorescence-activated cell scanning. They teach that subpopulations of cells were identified and quantified by surface staining with fluorescence labeled antibodies such as CD19-BV510 and CD27-BV605 (from BD-Biosciences, Franklin Lakes NJ, USD; Pg 2200 column right, third and fourth full paragraphs). They also teach that the biomarkers for memory B cells are CD19 and CD27 (Pg 2203 column right, Section titled “B-cell subsets”).
Since Moser et al. teaches that memory B cell populations in the blood samples of MS patients treated with cladribine were determined to have decreased by 87% to 95% compared to before cladribine treatment, therefore, as defined by instant claim 8, the deviations as taught by Moser et al. are indicative of early efficacy of said cladribine treatment and predicts response (as claimed).
Therefore, Moser et al. anticipates the instant claims above; and/or the instant claims above are obvious over Moser et al.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Yie-Chia Lee (Tonya) whose telephone number is (571)272-0123. The examiner can normally be reached Monday - Friday 7.30a - 3.30p Eastern Time Zone.
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/YIE-CHIA LEE (TONYA)/Examiner, Art Unit 1642
/SEAN E AEDER/Primary Examiner, Art Unit 1642
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