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 .
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Status of the Claims
Claims 1, 3-9, 12-21 and 23-25 are pending; claims 1, 3-8, 12, 15, 16-19, 23 and 24 are amended; claims 2, 10-11, 22 and 26-51 are cancelled; claims 12-14 and 24-25 are withdrawn. Claims 1, 3-9, 15-21 and 23 are examined below.
See 37 CFR 1.121, regarding claims 12, 24 and 25, if a withdrawn claim is currently amended, its status in the claim listing may be identified as "withdrawn— currently amended."
Priority
The present application was filed as a proper National Stage (371) entry of PCT Application No. PCT/EP2020/082068, filed 11/13/2020. Acknowledgment is also made of applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d) to Application Nos. EP19219889.2, filed on 12/27/2019, EP20158355.6, filed 02/19/2020, and EP20174174.1, filed 05/12/2020, with the European Patent Office.
Withdrawn Objections/Rejections
The rejection of claim 20 under 35 U.S.C. 112(b) is withdrawn upon being given further consideration (the limitation is considered to be broad, not indefinite).
The rejection of claim 22 under 35 U.S.C. 112(b) is withdrawn in response to Applicant’s amendments to the claims (claim 22 has been canceled by Applicant).
The rejection of claim 23 under 35 U.S.C. 112(b) is withdrawn in response to Applicant’s amendments to the claims.
Claim Rejections - 35 USC § 112
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 1, 3-9, 15-21 and 23 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.
The claimed invention recites a combination of biomarkers described in terms of their functional ability, namely the ability to use the panel to identify Sézary signature cells (e.g., claim 1). See similarly claim 15, correlating the frequency of cells with a diagnosis of Sézary Syndrome (see using the method of claim 1). See for example, independent claim 1 recite “A method for determining the frequence of Sézary signature cells in a plurality of cells”, the method comprising “determining the levels of expression of two or more biomarkers…determining the frequency of Sézary signature cells …based on the levels of expression…wherein the biomarkers comprise or consist of…” a, b, c or d As such, claim 1 encompasses indicating Sézary-signature cells based on any combination of TIGIT with the markers of groups a, b, c or d. Although Applicant has elected a specific panel of biomarkers (see discussed previously above, the panel as at claim 1 c), notably the independent claim is not limited to this specific panel of biomarkers.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP 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. See MPEP 2163.
Regarding Applicant’s actual reduction to practice, see Examples start at page 53 of the originally filed specification. Applicant used 53 samples to train a CellCnn neural network to distinguish between Sézary syndrome and non-Sézary syndrome (atopic dermatitis and healthy donor) samples (page 55), Applicant asserting that the CellCnn was able to robustly identify a biomarker from the discovery cohort data, however at the specification page 55 Applicant does not indicate the identity of this identified biomarker.
At page 55 Applicant’s specification indicates CellCnn was then trained using the full discovery dataset, input consisting of 1000 batches of 3000 cells chosen randomly from each sample independently, the CellCnn model run in classification mode, 20% of the samples set aside for validation during the training of the model. Applicant’s specification indicates 100% accuracy on both training and validation data, referencing Figure 2. The specification at page 55 reports using the learned weights from the CellCnn filter most strongly associated with Sézary syndrome samples, the inventors calculated a filter response score for every cell dataset, that the scores can be used to set a threshold to determine Sézary specific signature cells.
Applicant, at page 56, reports that in order to validate the Sézary-specific biomarker (the identity of “the biomarker” not identified at page 56), PBMCs were collected from an independent cohort of 33 subjects, 11 with Sézary syndrome, 11 with atopic dermatitis, 11 healthy donors. Applicant reports 0.81 sensitivity and 0.95 specificity for the predictions using the CellCnn network.
Regarding phenotypic characterization of the signature cells, see at pages 56-57, Applicant indicates parallel with CellCnn analysis, inventors performed clustering on the CyTOF data using FlowSOM based on the marker expression profiles CD4 T cells, CD8/CD8a Tcell, other T cells, B cells, NK cells, myeloid cells and pDCs, reporting that it was CD4+ T cells that showed in enrichment in Sézary syndrome versus non-Sézary syndrome samples.
At page 57, referring to the biomarkers shown at Figure 5, Applicant indicates the filters learned by CellCnn correspond to a set of weight for each measured protein “which can be either positive or negative”. The specification at page 57 indicates taken as a whole, these weights “may be considered to define the molecular profile of a theoretical group of cells that is strongly predictive of a given class label”.
Regarding Applicant’s reduction to practice as discussed/summarized in detail above, see specifically at page 58, Applicant identifies a preferred panel of biomarkers increased in cells specific to patients with Sézary syndrome (i.e., “positive biomarkers”), as well as those with levels decreased (“negative biomarkers”). Specifically see those listed at Table 3, reporting at Table 3 each panel with the corresponding median accuracy (using discovery cohort), SD accuracy (using discovery cohort), sensitivity (validation cohort) and specificity (validation cohort).
At Table 4, Applicant designates 19 marker panels used for a comparison of the sensitivity of the various panels versus four existing methods from the prior art (see shown at Table 5), Applicant remarks all the panels at Table 4 (using 15 patient cohort) were able to separate the classes of samples using CellCnn by defining a threshold on the CellCnn filter score (se page 58 of the specification and Table 4). The prior art methods (as indicated at table 5) appear to suggest that Applicant performed measurements on the prior art indicated panels/measurements, that the prior art panels were on the 15 patient cohort that Applicant’s own 19 panels were used on, the prior art measurements/panels including CD4/CD8 ratio, % CD4 CD7-, % CD4 CD26- and TCR clone (flow). It is not clear from Applicant’s originally filed specification what were the assay/technique parameters/conditions followed, other than that these prior art biomarker measurements were performed (i.e., that these panels were measured).
Importantly, Applicant’s actual reduction to practice specifically indicates two panels in particular as preferred panels, referring to panel A at Table 7, and Panel B at Table 9 (see originally filed specification at page 73), Applicant specifically refers to a 3 sequence strategy to indicate whether a patient is positive or negative for Sézary-Syndrome. See page 74, Applicant’s data for Applicant’s strategy only provided for specifically Panel A (reporting Panel A performance at page 74). However, regarding the strategies at page 74, Applicant’s strategy doesn’t indicate above what threshold/value is positive (see “XX%). Notably the presently recited claims are much broader in scope than Applicant’s actual reduction to practice (referring to the 3 sequential strategies indicated, and specific preferred panel of biomarkers).
As a result, Applicant’s actual reduction to practice appears to support Panel A as specifically tested and able to be used in order to identify Sézary signature cells.
Applicant’s specification does not support Applicant was in possession of the entire breadth of the claims as recited at independent claims 1 and 15, see regarding the breadth of the claims, in addition to determining frequence of Sézary signature cells in a plurality of cells, the claims also broadly encompass any combination of biomarkers (any combination of two or more), selected from groups a-d. Further, the claims (referring to at least independent claims) are not limited to any particular assay for such cells, or sample type (for example, while the reduction to practice is limited to cells associated with the skin, the claims are not limited). Combinations of biomarkers beyond Applicant’s tested specific panel for Sézary syndrome/sequential strategies from the examples (as discussed above) are not readily predictable in terms of their ability to achieve the function(s) as claimed. For example, regarding predictability, see Applicant’s originally filed specification (page 1) initial stages of Sézary syndrome are hampered by the occurrence of other diseases with similar symptoms including atopic dermatitis, chronic eczema, and other forms of non-specific dermatitis.
See further regarding unpredictability, although the claims as amended no long require that the combination include TIGIT, when using TIGIT as an example of one of the claimed markers, see for example Wen et al., A pan-cancer analysis revealing the role of TIGIT in tumor microenvironment, 11(22502), (2021), (12 pages), TIGIT is recognized as an immune checkpoint protein known to be expressed in many cancer types, not merely CTCL type cancers. It is not predictable that any combination of TIGIT and a biomarker(s) (at least two where one is TIGIT, for example) would correlate with Sézary Syndrome signature cells.
Same for the other biomarkers in Applicant’s claims/table 1, not all the claimed biomarkers are specific for/indicative of only Sézary syndrome cells. For example, see CN101885769A, CD4 is related to other diseases such as lymphocytic tumors, AIDS, rheumatoid arthritis, allograft organ transplant rejection (paras [0005]-[0006]). Shamah et al., US PG Pub No. 2010/0291575A1, CD4 and CD8 recognized related to HIV infection diagnosis (para [0138]). Ghanekar et al., US PG Pub No. 2018/0164287A1, para [0035], in some instances, biomarkers used in obtaining a Tuberculosis assessment include CD45RA, CD27.
While Applicant’s specification does acknowledge that there are various combinations of biomarkers, inclusive of species at Applicant’s claimed groups, that are recognized in the prior art to predictably correlate with signatures as claimed (Sézary syndrome, see pages 2-3 of the originally filed specification), Applicant’s independent claims are not limited to a predictable combination of biomarkers for a specific diagnosis and is much broader in scope. The claims, as discussed in detail above, are much broader in scope than Applicant’s actual reduction to practice. For all the reasons indicated in detail above, Applicant’s originally filed specification does not support that Applicant was in possession of the full scope of the claimed invention.
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, 3-9, 15-21 and 23 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.
Claim 1 recites “CD8/C8a”, the claim language is indefinite because it is not clear if this biomarker represents merely CD8 as in CD8 or CD8-alpha chain, or a ratio of CD8/CD8a, where CD8a represents alpha chain CD8. The claim is indefinite because is it not readily clear what is and is not encompassed by the recited language.
Claim 1 recites “determining the levels of expression of two or more biomarkers in a plurality of cells”, the claim reciting “wherein the biomarkers comprise or consist of:…”, the claim then reciting a)-d) wherein each of a)-d) is a group of biomarkers. The claim is indefinite it because it is not clear if the “two or more” are intended as two or more from any one group a-d, or if the two or more can be two or more where the markers are in different groups a-d. Further, the language “two or more” and “comprise or consist of” is indefinite claim language because the transitional language “comprise” is considered open language (could include other biomarkers, not limited to those recited) whereas the transitional language “consist of” is considered closed language, which contradicts the language “two or more” which is not particularly limited to any group a)-d).
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 1, 3-9, 15-21 and 23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to laws of nature/natural phenomena and abstract ideas without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
Claim 1 recites the method is “A method for determining the frequency of Sézary syndrome signature cells in a plurality of cells”, the active method steps reciting “determining the levels of expression of two or more biomarkers in a plurality of cells” and “determining the frequency…based on the levels of expression of the two or more biomarkers”, the claim limiting the biomarkers to those of recited at groups a), b), c) or d). The claim is tantamount to correlating the biomarkers, and as such the cells expressing the biomarkers, with a diagnosis that is Sézary syndrome. Further although claim 1 does not explicitly state a step/limitation that uses the word “comparing”, as discussed above, the claim does recite “determining the frequency…based on the levels of expression”, which is tantamount with mental activity, making an observation or judgement (i.e., the determination) based on the observed levels of expression.
Independent claim 15 recites more directly “a method for diagnosing a subject as having Sézary syndrome”, the claim determining frequency according to the method of claim 1, and further reciting a comparison step, “comparing the frequency of…determined in step (i) to the frequency…in a sample that has been obtained from a subject not suffering from Sézary syndrome, respectively and/or to the frequency of Sézary signature cells, respectively, in a sample that has been obtained from a subject with Sézary syndrome, respectively”, making a determination based on the comparison (see step iii).
The claims are directed to a natural relationship between the frequency of Sézary syndrome, i.e., the naturally occurring biomarkers expressed at each, and Sézary syndrome. The natural relationship is a law of nature. Similar concepts have been held by the courts to constitute law of nature/ natural phenomena, as in the identification of a correlation between the presence of in a bodily sample (such as blood or plasma) and cardiovascular disease risk in Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1361, 123 USPQ2d 1081, 1087 (Fed. Cir. 2017). In Mayo, the Supreme Court found that a claim was directed to a natural law, where the claim required administering a drug and determining the levels of a metabolite following administration, where the level of metabolite was indicative of a need to increase or decrease the dosage of the drug. See Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. 66, 74 (2012).
The instant claims are similar to those in Mayo as they involve a "relation itself [which] exists in principle apart from any human action" (id. at 77), namely the relationship between the naturally occurring levels of the expressed biomarkers, signature cells expressing the biomarkers and the presence of disease, either Sézary syndrome. The correlation is a judicial exception as it exists in principle apart from any human action; the correlation itself therefore cannot form the basis of eligibility. Further, it is naturally occurring phenomenon that cells expressing the markers, and the levels of the markers, are altered in relation to the disease(s) as claimed.
Additionally, regarding claim 1, as discussed in detail above although claim 1 does not explicitly state a step/limitation that uses the word “comparing”, as discussed above, the claim does recite “determining the frequency…based on the levels of expression”. See MPEP regarding what is considered groups of abstract ideas, the step of “determining” as recited amounts to an abstract idea because it is a mental process. For example, given broadest reasonable interpretation, “determining the frequency” as claimed, based on the expression levels amounts to a concept performed in the human mind, namely observing the expression levels and thinking above the levels to form an evaluation/judgement as to the frequency of cells in the plurality of cells related to cell signature for the disease(s) (Sézary syndrome).
Regarding claim 15, the “comparing step” also expresses an abstract idea, namely mental processes/concepts performed in the human mind (for example, such as a practitioner simply thinking about the measured expression levels in relation to the amount in a reference/control population and making an evaluation, judgement, or opinion). The claims, under broadest reasonable interpretation, cover performance of the diagnosis solely within the human mind, or by a human using a pen and paper (with regards to the independent claim, at least). Comparing information regarding a sample to a control or target data represents abstract ideas.
Similar concepts involving comparing information regarding a sample or test subject to a control or target data have been held to be an "abstract mental process", as in University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 113 USPQ2d 1241 (Fed. Cir. 2014) which involved "comparing BRCA sequences and determining the existence of alterations", the collecting and comparing of known information in Classen, the comparing information regarding a sample or test subject to a control or target data in Ambry and Myriad CAFC, as well as Mayo.
Step 2A, Prong 2
The above discussed steps/limitations are insufficient to integrate the judicial exception into a practical application thereof because the steps/limitations correspond to the judicial exceptions themselves (not a practical application thereof, i.e., natural correlation, abstract ideas).
None of the independent claims themselves recite further steps, elements or limitations which amount to integration into a practical application (there are no steps/elements that further apply, rely on, or use the judicial exceptions in a way that amounts to an integration into a practical application).
Dependent claim 5 further recites “wherein a classifier algorithm is used to distinguish between Sézary signature cell and non-Sézary signature cell”, claim 6 reciting “a convolution neural network is used to distinguish between a Sézary signature cell and a non-Sézary signature cell” (see similarly claims 16 and 17, claim 17 however recites “a convolution neural network and/or logistic regression”).
Although there are dependent claims (claims 5, 6, 16 and 17) that specifically recite that a classifier is used, namely that a CNN or logistic regression is used in order to distinguish cells based on the expression levels of the proteins, it is necessary to determine whether the claim simply recites the judicial exception with the words “apply it” (or an equivalent), such as mere instructions to implement an abstract idea on a computer. In making the determination, it is necessary to consider (1) whether the claim recites only the idea of a solution or outcome, i.e., the claim fails to recite the details of how a solution to a problem is accomplished; (2) whether the claim invokes computers or other machinery as a tool to perform an existing process; and (3) the particularity or generality of the application of the judicial exception. (MPEP 2106.05(f). In the instant case, the claims recite no detail about a particular CNN or logistics regression, or how the CNN operates. In the present case, the recitation directed to a CNN (or logistics regression) is used to generally apply the abstract idea (i.e., to perform mathematical calculations) without placing any limitations on how the CNN (or algorithm) operates to achieve the distinguishing step/classification of the cells as signature cells. The claims omit any details as to how the CNN, for example, solves a technical problem. The claim invokes a generic algorithm (CNN or logistics regression) merely as a tool for making the determination/distinction between cells. As a result, the limitation represents no more than mere instructions to apply the judicial exception on a computer, and at most merely links the use of the judicial exception to the technological environment of computers.
Further, dependent claim limitations reciting that levels are determined using antibody-based assay (claim 8), antibody-based flow cytometry or mass cytometry analysis (claim 9), are limitations directed at the gathering of the data used in the judicial exceptions. Steps performed merely to obtain the data do not go beyond insignificant pre-solution activity, i.e., data gathering steps necessary to use the correlation/abstract idea. These claim limitations fail to further apply, rely on or use the judicial exception in way to amount to integration of the judicial exception into a practical application.
Additional, limitations directed to the panel and/or number of biomarkers, as well as the subject population, while further limiting the judicial exceptions themselves, do not further apply, rely on or use the judicial exceptions.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
The additional elements of the claims also do not add significantly more to the judicial exception(s). For example, immunophenotyping cells based on biomarker expression is well known and routinely performed in the assay art. Although Applicant’s claims recite various combinations of biomarkers, the claims are not limited to any particular panel which would amount to more than what was considered routine and conventional in the assay art. For example, see Applicant’s originally filed specification at pages 2-3, which supports that many of the biomarkers recited at the claimed Table, as well as the act of using panels of biomarker expressions (measured by flow cytometry) to indicated cells, for Sézary Syndrome is routine and conventional in the art at the time.
See also the cited prior art, Jariwala et al., TIGIT and Helios Are Highly Expressed on CD4+ T Cells in Sézary Syndrome Patients, Journal of Investigative Dermatology, (2017), 137, p. 257-260 (IDS entered 06/27/2022), supporting TIGIT is an expressed biomarker correlating with Sézary syndrome (see page 258, col. 1, para 2). Novelli et al., Blood Flow Cytometry in Sézary Syndrome, AJCP, (2015), 143, p. 57-69, Novelli teach a first-step panel for Sézary syndrome should include evaluation of CD26, CD27, CD28, CD38, CD45RO and CD45RA, in addition to T cell markers CD2, CD4, CD7, CD8 and CD3 and CD45 (see page 67, col. 1, last paragraph, panel of Novelli includes almost all the markers of Applicant’s elected species). van Dongen, WO2010/140885A1, van Dongen et al. teach at Table 3, phenotypic characterization identification of Sézary syndrome see the combination including several similar biomarkers as in Novelli, for example Van Dongen teach CD4, CD45, CD7, CD26, CD3 and CD8.
The claims fail to recite additional steps or elements which amount to more than that which was well-known, routine and conventional in the assay art.
Additionally, limitations that are necessary for all practical applications of a judicial exception, such that everyone practicing the judicial exception would be required to perform those steps or every product embodying that judicial exception would be required to include those features, would not be sufficient to confer patent eligibility. In this case, everyone practicing the judicial exception would need to determine expression levels of the markers as claimed.
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 determining expression level (by antibody based methods, by flow cytometry). See also MPEP 2106.05(g).
Whether considered alone, or as an ordered combination, none of the recited limitations amount to more than that which was well known routine and conventional. See as discussed in detail previously above, although the claims recite an algorithm, or further a CNN, these additional elements represent merely instructions to apply the exceptions and insignificant extra-solution activity.
For all of these reasons, the claims are rejected under 35 U.S.C. 101.
Although Applicant has elected a specific panel of biomarkers, and the claims are examined in light of Applicant’s elected species (the panel addressed in rejection below under 35 U.S.C. 103), the present rejection under 35 U.S.C. 102 is also made in the interest of compact prosecution, as the claims as presently recited are not specifically limited to Applicant’s elected species and encompass less biomarkers than the elected panel. The search has not been extended to cover all non-elected species.
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 and 7-9 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jariwala et al., TIGIT and Helios Are Highly Expressed on CD4+ T Cells in Sézary Syndrome Patients, Journal of Investigative Dermatology, (2017), 137, p. 257-260 (IDS entered 06/27/2022).
Jariwala et al. teach significantly increased percentages of TIGIT+ and CD4+ T cells in patients with Sézary syndrome (see page 258, col. 1, para 2). Jariwala teach determining the frequence of the cells (Sézary syndrome signature cells) by determining the level of expression of the biomarkers and determining the frequency based on the expression (expression in comparison to atopic dermatitis, psoriasis and control skin, see page 258 as cited, and further Figure 1). See further comprising determining expression of an additional biomarker (e.g., CD26, see page 258, col. 2, para 2 to col. 3, Figure 2).
Regarding claim 7, Jariwala is teaching human subjects.
Regarding claims 8 and 9, Jariwala teach determination by antibody based assay (flow cytometry, see Figure 1 caption).
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, 3-4, 7-9, 15, 18-21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Novelli et al., Blood Flow Cytometry in Sézary Syndrome, AJCP, (2015), 143, p. 57-69, in view of Jariwala et al., van Dongen, WO2010/140885A1 and Valkirs et al., US PG Pub No. 2003/0109420.
Novelli et al. is teaching methods comprising determining the level of expression of a panel of biomarkers (two or more, see below, teaching most of Applicant’s elected panel species) in a plurality of cells, determining correlation (frequency) based on a measurement of expression (see Novelli teach flow cytometry to screen blood sample, page 58, end of col. 1 to page 59, col. 1).
Novelli et al. teach a first-step panel for Sézary syndrome should include evaluation of CD26, CD27, CD28, CD38, CD45RO and CD45RA, in addition to T cell markers CD2, CD4, CD7, CD8 and CD3 and CD45 (see page 67, col. 1, last paragraph, panel of Novelli includes almost all the markers of Applicant’s elected species). See Novelli teach the most commonly observed lymphocyte immunophenotypic pattern in patients with Sézary syndrome was CD3+, CD5+, CD4+, CD8-, CD27+, CD28+ and CD45RO+, reporting the most common aberrancy at diagnosis was lack of CD26 expression (page 60-61). Novelli confirmed relevance of CD26 negativity for diagnostic purposes.
Novelli includes all markers of Applicant’s elected species (amended claim 1, at c), except fails to teach TIGIT.
Jariwala et al. teach significantly increased percentages of TIGIT+ and CD4+ T cells in patients with Sézary syndrome (see page 258, col. 1, para 2). Further report CD26- expression in CD4+ T cells in Sézary syndrome patients (page 257, col. 1, last paragraph, page 258, col. 2, para 2).
van Dongen teach determining the frequency of Sézary signature cells in a plurality of cells, comprising determining the levels of expression of two or more biomarkers in a plurality, and determining (frequency) of Sézary signature cells based on the expression (methods comprising flow cytometry, provide sample, contact with reagent, analyze by flow cytometer, , see Euroflow panels, pages 11-13, Table 3). Van Dongen et al. teach at Table 3, phenotypic characterization identification of Sézary syndrome see the combination including several similar biomarkers as in Novelli, for example Van Dongen teach CD4, CD45, CD7, CD26, CD3 and CD8, of theses each of CD4, CD45, CD3 and CD8 are indicated to be backbone marker. See at page18, lines 14-24, backbone markers aim at providing delineation of the groups of cells of interest, that backbone markers are combined with a variable number of additional characterization markers which further attribute to discrimination/distinction.
Valkirs teach methods of diagnosis and evaluation, specifically regarding early detection and differentiation of a health condition based on sample analysis regarding the presence and amount of members of a panel of markers (see abstract). See paras [0017], [0031], [0107] and [0184], Valkirs teach by combining a plurality of markers one can increase the predictive value of an analysis in comparison to an analysis of individual markers; and particularly that the multi-marker strategy presents benefits with regard to risk stratification (see para [0184]).
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention, to have modified the panel of Novelli et al., to further measure expression of the biomarker TIGIT because it was known that TIGIT was also significantly increased in Sézary Syndrome (in CD4+ T cells related to SS, see Jariwala et al.). One having ordinary skill in the art would have been motivated to further include TIGIT because it was well known at the time to include variable number of additional characterization markers to attribute to discrimination (van Dongen). In particular, both van Dongen and Valkirs support that including additional markers in a panel intended for diagnostic characterization can improve/increase the ability of the panel to be predictive/diagnostically discriminatory.
One having ordinary skill in the art would have had a reasonable expectation of success combining TIGIT with the panel as taught by Novelli because the prior art already recognized combining additional biomarkers with main “backbone” recognized markers into a single panel to improve diagnostic detection/prediction.
Regarding claims 3-4 and 10-11, see the prior art addresses Applicant’s elected panel of biomarkers (comprising 9 biomarkers, claim 10 the elected panel at panel r of claim 10, and claim 11).
Regarding claim 7, Novelli is teaching human cells.
Regarding claims 8-9, see Novelli is teaching antibody based assay that is flow cytometry (page 58, col. 2, to page 59).
Regarding claims 15 and 18, Novelli et al. and the cited art above teach methods substantially as claimed, Novelli et al. is teaching immunophenotyping in patients diagnosed with Sézary Syndrome (retrospective review indicating an expression pattern observed as compared to those without Sézary Syndrome). Because Novelli is a retrospective study, Novelli does not specifically teach a method of diagnosis, performing the method (claim 1), comparing the frequency of cells exhibiting Sézary Syndrome signature (expressing the biomarkers as in the panel taught by the combined prior art above) in a sample to that of a sample obtained from someone not suffering from Sézary syndrome, determining the subject has having Sézary syndrome if the frequency of cells is higher compared to those not having Sézary syndrome.
However, Novelli does teach their panel intended for diagnosis of Sézary Syndrome (see page 68, end of col. 1 “we believe that the first-step panel for SS diagnosis should include the evaluation of…”.
It would have been prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method as taught by Novelli and the cited art in order to apply the method for diagnosis (i.e., to detect in an unknown sample, the frequency of cells exhibiting the Sézary syndrome signature biomarkers as dictated by the panel taught by the cited prior art, and compare it to the frequency of cells in a subject that does not suffer from Sézary , wherein a higher frequency of cells indicates Sézary Syndrome) because Novelli is specifically teaching the panel for the intention of diagnostics (as a first step panel for diagnosis, see specifically Novelli is suggesting the panel to indicate cells correlating with Sézary Syndrome diagnosis). Further, because Novelli teach the panel for this purpose, one having ordinary skill in the art would have a reasonable expectation of success.
Regarding claim 19-21, Novelli further teach their methods comprising one or more other diagnostic tests and/or additional information obtained about the subjects, for example, determinations such as age and CD4/CD8 ratio (page 59, col. 2, last paragraph).
Regarding claim 23, Novelli is teaching blood samples (peripheral blood lymphocyte immunophenotyping performed on samples that are blood samples, see page 58, col. 1, last paragraph).
Claim(s) 5, 6, 16 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Novelli et al. in view of Jariwala et al., van Dongen et al. and Valkirs et al., as applied to claims 1 and 15 above, and further in view of Buyssens, P., et al., (2013). Multiscale Convolutional Neural Networks for Vision–Based Classification of Cells. In: Lee, K.M., Matsushita, Y., Rehg, J.M., Hu, Z. (eds) Computer Vision – ACCV 2012. ACCV 2012. Lecture Notes in Computer Science, vol 7725. Springer, Berlin, Heidelberg. P. 342-352. https://doi.org/10.1007/978-3-642-37444-9_27.
Novelli et al. and the cited prior art teach methods substantially as claimed, however, Novelli fails to teach using a classifier algorithm to distinguish Sézary signature cells from non-Sézary syndrome signature cells (claim 5), and fails to teach an algorithm comprising a convolution neural network (claim 6).
Buyssens et al. teach multiscale convolution neural networks (multi-layer neural networks that are specialized in pattern recognition tasks, see page 343, section 2) for the purpose of better classification of cells (see abstract at page 342). Buyssens et al. teach interest in computer-aided diagnosis through image processing (page 342), teaching that automatic salient feature extraction by a computer saves time, and allows for safer and faster diagnosis. Buyssens et al. teach benefits of using MCNN are better classification rates than classical state-of-the art approaches (for cell classification) (see page 351, conclusion).
It would have been further prima facie obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to have modified the method as taught by Novelli et al. and the cited art to further use a classifier algorithm, such as a CNN (a classifier algorithm, such as the MCNN of Buyssens et al.) in order to distinguish cells because Buyssens teach safer, faster diagnosis, with better classification rates. The modification would be applying an art recognized technique to achieve an improved diagnosis/classification. One having ordinary skill in the art would have a reasonable expectation of success given that this type of CNN is specifically taught for the purposes of cell classification (Buyssens), as such the modification would be applying a known technique for its art intended purpose, and be expected to improve classification.
Response to Arguments
Applicant's arguments filed 01/21/2026 have been fully considered but they are not persuasive for the following reasons.
Regarding the rejection of claims under 35 U.S.C. 112(b), at remarks pages 11-13 Applicant indicates they disagree with the rejection and refer to amendments to the claims to overcome the rejection (namely, amendments limiting to specific biomarker panels and detection of Sezary Syndrome). However, this argument is not persuasive, see for example, the claims even as amended still recite “determining the expression of two or more biomarkers”, and therefore the claims are not limited to a particular/specific panel as argued.
Further, see the rejection as set forth in detail above, regarding Applicant’s reduction to practice as discussed/summarized in detail above, see specifically at page 58, Applicant identifies a preferred panel of biomarkers increased in cells specific to patients with Sézary syndrome (i.e., “positive biomarkers”), as well as those with levels decreased (“negative biomarkers”). Specifically see those listed at Table 3, reporting at Table 3 each panel with the corresponding median accuracy (using discovery cohort), SD accuracy (using discovery cohort), sensitivity (validation cohort) and specificity (validation cohort).
Applicant’s actual reduction to practice specifically indicates two panels in particular as preferred panels, referring to panel A at Table 7, and Panel B at Table 9 (see originally filed specification at page 73), Applicant specifically refers to a 3 sequence strategy to indicate whether a patient is positive or negative for Sézary-Syndrome. See page 74, Applicant’s data for Applicant’s strategy only provided for specifically Panel A (reporting Panel A performance at page 74). However, regarding the strategies at page 74, Applicant’s strategy doesn’t indicate above what threshold/value is positive (see “XX%). Notably the presently recited claims are much broader in scope than Applicant’s actual reduction to practice (referring to the 3 sequential strategies indicated, and specific preferred panel of biomarkers). As a result, Applicant’s actual reduction to practice appears to support Panel A as specifically tested and able to be used in order to identify Sézary signature cells. Applicant’s specification does not support Applicant was in possession of the entire breadth of the claims as recited at independent claims 1
Regarding the rejection of claims under 35 U.S.C. 112(b), over the limitation “CD8/CD8a”, Applicant argues the claimed limitation is not indefinite because CD8/CD8a refers to “the CD8 antigen, specifically nothing the alpha chain (CD8a)” (see remarks page 13). Applicant argues this format is well-recognized usage in the art, and argues that in standard immunology the CD8 co-receptor is typically a heterodimer of an alpha and beta chain, but the alpha chain (CD8a) is the defining component often targeted by diagnostic antibodies to identify cytotoxic T cells. Applicant asserts (page 13) that “CD8/CD8a” simply indicates that the biomarker is CD8, which may be identified specifically via its alpha chain, not a mathematical ratio of CD8 to CD8a.
However, Applicant’s argument is not persuasive because the terminology “CD8” and “CD8a” are not identical in scope, CD8 is a protein with two isoforms (alpha and beta), and CD8a specifically refers to the alpha isoform of the protein, further at other places in the present claims (specifically, for example claim 20), Applicant does use “/” to indicate a ratio (see at claim 20, CD4/CD8 ratio). It is suggested, that if Applicant intends to refer to CD8 generally, Applicant amend in order to recite CD8, and if Applicant intends to recite the alpha isoform of the protein, then Applicant amend in order to recite CD8a in order to improve clarity.
Regarding the limitation “cell count analysis” Applicant argues this limitation refers to “one or more other diagnostic tests” performed in addition to the method of claim 1, that “in clinical practice, “cell count analysis” typically refers to standard Complete Blood Count (CBC) or absolute lymphocyte count, a gross measurement of total cell numbers per volume of blood, distinct from flow-cytometry immunophenotyping used to determine the frequency of the specific Sezary signature (remarks page 14). Applicant argues the limitation is not redundant or confusing. Although there is no support in the originally filed specification which supports limiting this limitation to something such as CBC, the rejection is withdrawn upon further consideration. Specifically, upon further consideration, the limitation is considered broad and not indefinite.
Regarding the rejection of claim 22 under 35 U.S.C. 112(b), see as indicated in detail above, the rejection is withdrawn.
Regarding the rejection of claims under 35 U.S.C. 101, Applicant refers to amendments to the claims to overcome the rejection (remarks page 15). Applicant remarks that a single biomarker for Sezary signature cells has not been found, that instead a variety of biomarkers in a panel have been used for identification. Applicant argues the claimed invention is directed to the discovery of four panels of biomarkers that provide more effective identification, that this is practical application of determining levels of expression of various yet specific biomarkers to determine the frequency of Sezary signature cells. Applicant argues that the specific of the biomarker panel renders the claim more than a mere natural phenomenon or abstract idea (remarks page 15).
This argument is not persuasive, the correlation itself is the judicial exception, not a practical application thereof. In order for a limitation to amount to “integration into a practical application”, the additional element or combination of additional elements (i.e., the limitations recited in addition to the judicial exception) must apply, rely on or use the judicial exception in a manner that imposes meaningful limit on the judicial exception. In the present case, in addition to the natural correlation/abstract ideas, there are no additional claimed elements which apply, rely on or use the judicial exception. Regarding step 2A, Prong 2 considerations under 35 U.S.C. 101, the detection of the biomarkers themselves are not sufficient to integrate into a practical application.
At remarks pages 15-16 Applicant further argues that the claimed invention contributes an inventive concept and is thus useful and patent eligible. Applicant argues that the Examiner alleges that using the biomarker panels claimed for SS is routine and conventional; however, in response and in order to clarify, the rejection maintains that the active method steps which are recited in addition to the judicial exception (the determining the biomarker step(s)) are steps considered routine and conventional. The correlation of the determined biomarkers with SS is the judicial exception. Further, in response to remarks, the pending claims are not limited to the panels of a-d, rather see the claim encompasses at least two markers from those recited.
Regarding the rejection of claims under 35 U.S.C. 102, at remarks page 16 Applicant remarks that the biomarker panels of claim 1 are more precisely defined and as such the rejection should be withdrawn. Although claim 1 is amended to recite groups of biomarkers a-d, as noted previously above, the claim still also recites “determining the levels of expression of two or more biomarkers in a plurality of cells”. As such, the claims are not limited to any particular panel/combination as set forth in a-d. The rejection is maintained.
Regarding the rejection of claims under 35 U.S.C. 103, Applicant remarks that the panel at claim 1, c) corresponds to Applicant’s elected panel of biomarkers. Applicant argues that results of Panel are shown at Table 7 as Panel A, that the panel achieved 100% specificity, that the panel achieves a superior outcome compared to the prior art. See at remarks page 17 Applicant argues the Novelli does not teach 100% selectivity, further remarking that the claimed panel does not require the presence of the biomarkers required by Novelli. However, Applicant’s arguments are not persuasive, these arguments are not commensurate in scope with the claims, which see as noted previously above, the present claims are not limited to any particular panel of biomarkers (for example, the claims recite two or more biomarkers, and also recited “comprise or consist of”). The claimed invention is obvious over the prior art, the combination of the prior art does support that the claimed panel for SS (a panel comprising at least those markers of the elected panel) is obvious over the prior art.
Arguments specific to the remaining dependent claims (remarks page 18) refer to the reasoning applied to the independent claim above. As such, the rejections are maintained for the reasons as indicated.
The rejection of claim 22 is withdrawn as indicated above (claim 22 is canceled by Applicant).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Correspondence
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/ELLEN J MARCSISIN/ Primary Examiner, Art Unit 1677
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