DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election of (i) the combination of the BACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 genes; (ii) methods which detect nucleic acid levels; and (iii) inflammatory bowel disease. in the reply filed on 06 April 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim Status
3. Claims 1-3, 5-6 and 11-23 are pending.
Claims 1, 3, and 11 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 2, 5, 6, and 12-23 read on the elected invention and have been examined herein. It is noted that each of the claims encompass the non-elected species of methods which assay for proteins and claims 18 and 19 encompass non-elected subject matter of disorders other than an inflammatory bowel disorder. Prior to the allowance of claims, any non-elected subject matter which has not been rejoined with the elected subject matter will be required to be removed from the claims.
Objection to Drawings / Objection to the Specification
4. The drawings are objected to under 37 CFR 1.83(a). The specification describes Figure 1 in terms of particular colors – i.e. red and cyan (see, for example, p. 6, line 31 and p. 7, line 3). However, the figures have been filed in black and white. Thus, the description of the figures in the specification is not consistent with the drawing and the specification is thereby also objected to.
If the drawings are intended to be in black and white, the specification should be amended to delete the reference to the recited colors. Alternatively, corrected drawing sheets in compliance with 37 CFR 1.121(d) are required. Note that color drawings are only accepted on rare occasions when they are the only practical medium by which to disclose the subject matter to be patented. See MPEP 608.02(VIII).
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.
If color photographs or color drawings are submitted, it is noted that color photographs and color drawings are not accepted unless a petition filed under 37 CFR 1.84(a)(2) is granted.
A petition for color drawings must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via EFS-Web or three sets of color drawings or color photographs, as appropriate, if not submitted via EFS-Web, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Appropriate correction is required.
Claim Interpretation
5. The claims recite “(a) contacting blood cells of the subject with the agent; (b) measuring the expression of each of the genes BACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 in said blood cells of the subject.” The specification teaches “When the contacting is carried out in vivo, the candidate agent is provided to the subject and following the allotted length of time, blood cells are retrieved from the subject” (para [0089]; note that paragraph numbering herein is with respect to the published application). Accordingly, while the claims encompass methods wherein the contacting step is performed in vivo (or ex vivo), the claims are considered to require measuring the expression of the genes ex vivo - i.e., in blood cells retrieved / obtained from the subject.
Claim Rejections - 35 USC § 101
6. 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 2, 5, 6, and 12-23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between the expression level of the BACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 genes and immune age. For instance, the claims recite “obtaining an immune age value based on the expression of said at least genes.” As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.”
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
The claims require performing a step of "comparing" immune age values. Neither the specification nor the claims set forth a limiting definition for "comparing" and the claims do not set forth how “comparing” is accomplished. The broadest reasonable interpretation of the “comparing” step is that this step may be accomplished by critical thinking processes. Such “comparing” thereby encompasses only an abstract idea / process.
The claims also require “obtaining” an immune age value based on the expression of said at least genes. As broadly recited this step may be accomplished by reading information in a report or database regarding a subject’s immune age that has been calculated. Reading information in a report or database encompasses only an abstract idea / process. Alternatively, the obtaining may be performed by a practioner calculating an immune value using pen and paper or a generic computer or algorithm.
However, the use of pen and paper or a generic computer or software program to implement an abstract idea does not itself impart patent eligibility.
As stated in MPEP 2106.04(a)(2) III “The courts do not distinguish between mental processes that are performed entirely in the human mind and mental processes that require a human to use a physical aid (e.g., pen and paper or a slide rule) to perform the claim limitation” and that “Nor do the courts distinguish between claims that recite mental processes performed by humans and claims that recite mental processes performed on a computer.”
Thereby, the use of pen and paper or a generic computer to apply a generic algorithm to obtain an immune age value does not constitute something more than an abstract idea.
To any extent that the obtaining / calculating an immune age value is intended to require using a particular mathematical formula, Applicant’s attention is directed to MPEP 2106.04(a)(2):
“A claim that recites a mathematical calculation, when the claim is given its broadest reasonable interpretation in light of the specification, will be considered as falling within the “mathematical concepts” grouping. A mathematical calculation is a mathematical operation (such as multiplication) or an act of calculating using mathematical methods to determine a variable or number, e.g., performing an arithmetic operation such as exponentiation. There is no particular word or set of words that indicates a claim recites a mathematical calculation. That is, a claim does not have to recite the word “calculating” in order to be considered a mathematical calculation. For example, a step of “determining” a variable or number using mathematical methods or “performing” a mathematical operation may also be considered mathematical calculations when the broadest reasonable interpretation of the claim in light of the specification encompasses a mathematical calculation.”
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s). The additionally recited steps of contacting blood cells with an agent and measuring gene expression levels are part of the data gathering process necessary to observe the judicial exception. The contacting step is also extra-solution activity.. The contacting and measuring steps do not practically apply the judicial exception.
The claims also recite a step of “administering the agent to the subject.” The claims do not clarify whether the administering step is part of or distinct from “contacting blood cells of the subject with the agent.” Nor do the claims require that the administering step is performed after step (d). Note that in view of the open claim language of “comprising,” the steps of the claim may be performed in any order. Accordingly, the administering step may also be part of the data gathering process necessary to observe the judicial exception.
Regarding the contacting step and the embodiment in which administering is performed prior to measuring, Applicant’s attention is directed to MPEP § 2106.04(d)(2)(c), which states:
“The treatment or prophylaxis limitation must impose meaningful limits on the judicial exception, and cannot be extra-solution activity or a field-of-use. For example, consider a claim that recites (a) administering rabies and feline leukemia vaccines to a first group of domestic cats in accordance with different vaccination schedules, and (b) analyzing information about the vaccination schedules and whether the cats later developed chronic immune-mediated disorders to determine a lowest-risk vaccination schedule. Step (b) falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). While step (a) administers vaccines to the cats, this administration is performed in order to gather data for the mental analysis step, and is a necessary precursor for all uses of the recited exception. It is thus extra-solution activity, and does not integrate the judicial exception into a practical application.”
To the extent that the administering step is intended to be performed after step (d), this step is not considered to be a practical application of the judicial exception because the claim encompasses methods in which the agent is administered irregardless of whether there is a decrease in the immune age of the subject. That is, the claims encompass methods wherein the subject’s immune age increases and wherein no change in the subject’s immune age is detected. Note that the phrase “wherein a decrease in the immune age of the subject is indicative that the agent has therapeutic efficacy for treating the immune-related disorder” indicates only a property of a decrease in the immune age. The claims do not require that the method is one in which the immune age of the subject is determined to be decreased following the contacting, measuring and comparing steps. Accordingly, the administering step does not integrate the judicial exception into a practical application.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited step of contacting blood cells with an agent and measuring gene expression are recited at a high degree of generality and were well-known, routine and conventional in the prior art.
This finding is evidenced by the teachings in the specification. For instance, the specification states “Any isolation method that results in extracted RNA may be used in the practice of the present invention….Methods of RNA extraction are well-known in the art and further described herein under” (see para [0155-0156]). See para [0165] which teaches that RNA hybridization methods were well-known in the prior art; and para [0170] and [0208] which teach that RNA and protein detection methods were well-known in the prior art.
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
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);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite detecting the expression of particular genes, the identity of the genes is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence so as to add something ‘significantly more’ to the recited judicial exceptions.
Further, to any extent that the “obtaining” step is intended to require a computer, MPEP 2106.05(a) states that ”Limitations that the courts have found not to be enough to qualify as “significantly more” when recited in a claim with a judicial exception include: i. Adding the words “apply it” (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer, e.g., a limitation indicating that a particular function such as creating and maintaining electronic records is performed by a computer, as discussed in Alice Corp., 134 S. Ct. at 2360, 110 USPQ2d at 1984 (see MPEP § 2106.05(f))”
In Mayo v. Prometheus, the Supreme Court stated: "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
7. 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 2, 5, 6, 12-17 and 20-23 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.
Claims 2, 5, 6, 12-17 and 20-23 are indefinite over the recitation of “immune related disorder” / “immune-related disorder.” The specification does not provide a limiting definition for this phrase and there is no art recognized definition for this phrase. It is unclear as to what disorders are encompassed and what disorders are not encompassed by this phrase. For instance, it is not clear as to whether “immune related” encompasses any disorder that is a side-effect / symptom of a disorder such as an autoimmune disease, including stress, sleep apnea or fatigue or if this includes an infectious diseases which trigger changes in immune cells. The metes and bounds of the claimed subject matter are not clear.
Claim Rejections - 35 USC § 112(a) - Enablement
8. 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 2, 5, 6, and 12-23 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 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 following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
The claims are drawn to methods for treating any immune related disorder, including any inflammatory bowel disease (claim 18) and particularly Crohn’s disease (CD) or ulcerative colitis (UC) in any human or non-human subject in need thereof comprising: (a) contacting blood cells, in vivo or ex vivo, of the subject with any agent; (b) measuring the expression of each of the genes BACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 in the blood cells of the subject; (c) obtaining an immune age value based on the expression of said at least genes; (d) comparing the immune age value with an immune age value of the subject calculated on the basis of expression of said genes in blood cells of the subject, in the absence of said agent, wherein a decrease in the immune age of the subject is indicative that the agent has therapeutic efficacy for treating the immune-related disorder; and (e) administering the agent to the subject.
Regarding “immune age,” the specification (para [0128]) states:
“The term “immune age” refers to the approximate age of a subject's immune system. This may be an absolute measurement or a relative measurement. The immune age is an artificial score based on the frequency of the particular cell types (or expression level of particular genes, as described herein below). In one embodiment the immune age increases with the frequency of the particular cell types. Thus, in this embodiment the higher the immune age of the subject, the more deleterious. In another embodiment, the immune age decreases with the frequency of the particular cell types. Thus, in this embodiment, the lower the immune age of the subject, the more deleterious.”
These teachings make clear that a subject’s immune age value is an “artificial score” that is based in part on the particular cell types in a sample, which cell types may be inferred by gene expression levels. The specification does not set forth the complete process for calculating an immune age value, such as a particular formula. The teachings in the specification do not provide sufficient guidance and direction as to how to predictably calculate a subject’s immune age value based on the expression of the 8 genes of claim 2 or based on the full set of 57 genes disclosed in the specification.
The specification (para [0218] provides an example in which Crohn’s disease patients were treated with Infliximab and RNA levels of the panel of 57 genes disclosed therein were determined. It is stated:
“The immune-age of the CD patients was estimated by using single-sample GSEA algorithm (Barbie D A et al. Nature 462, 108-112 (2009)). An external IBD (CD and UC) disease specific molecular response axis was used to describe the patients' dynamics by generating a PCA on differential gene expression between active and in-active disease states treated with variety of treatment regimens (using public data, GSE94648).”
These teachings indicate that control populations of subjects having active and inactive CD and UC disease states were used as part of the process for calculating an immune age, but do not provide any specifics as to how the immune age value is calculated based on the claimed set of 8 genes. However, sufficient details were not provided as to how the immune age values were calculated.
In Table 9 of the specification, it is disclosed that the expression level of the presently claimed set of 8 genes were either increased or decreased as immune age increases. For instance, it is disclosed that the level of BACH2 RNA decreases with increasing immune age. However, the specification does not teach how to use the information regarding an increase or decrease in the expression level of the 8 gene panel to calculate an immune age value, particularly as indicative of the efficacy of any agent to treat any immune-related disorder in a human subject or non-human mammalian subject.
The specification (para [0129]) also teaches: “details of establishing immune age are provided in WO2019215740, the contents of which are incorporated herein by reference.”
The WO2019215740 document (cited in the IDS) is co-authored by present inventors Shai S. Shen-Orr and Ayelet Alpert. The document teaches calculating an immune age (IMM-age) score using the expression level of a set of 121 genes or a subset of 57 genes. Therein, IMM-age scores were calculated for subjects having cardiovascular disease. It is stated that “For the cardiovascular association analysis, the IMM-AGE score was adjusted by linear regression to the cardiovascular covariates used for estimating the ASCVD clinical risk score, specifically: age, gender, smoking status, diabetes, total cholesterol, HDL cholesterol, and blood pressure” (para [0133]). The document teaches that a control population is used to determine a relative immune age score for a subject:
“[0131] IMM-AGE approximation : Of the 121 genes that were identified as consistently and significantly changing along the trajectory, 103 genes were also present in the Framingham gene-expression dataset. To reduce the technical noise stemming from changing the gene- expression dataset, what may influence the inter-gene correlation relationships, we refined this gene-set and chose only those 57 genes that were highly correlated with the main PCA axis (absolute Pearson > 0.4), an axis that significantly and consistently reflected the calculated IMM-AGE scores in our cohort across years (data not shown). We quantified the enrichment of this gene-set in each participant of the Framingham study using single-sample gene-set enrichment projection (ssGSEA) and used the resulting enrichment scores as an approximation of the IMM-AGE scores of the Framingham participants. To improve the correspondence between the IMM-AGE score and chronological age, we applied linear scaling on the IMM-AGE scores that is based on a linear regression of the IMM-AGE scores against chronological age using the Offspring cohort individuals, a cohort with a relatively homogeneous range of ages resembling the one observed in our cohort. A linear model of the resulting scaled IMM-AGE scores against chronological age had slope and intercept equal to 1 and 0, respectively.”
However, these teachings do not provide a clear description of how an immune age value is calculated using the expression level of the 8 genes of ACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 for subjects having any immune related disorder. Even using the 57 gene panel, there is not sufficient guidance as to how to immune age value is calculated based only on the gene expression levels.
Without clear guidance as to how to predictably determine an immune age value using the expression level of ACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4, it would require undue experimentation for the skilled artisan to practice the claimed invention. Note that the present claims specifically require obtaining an immune age value for a subject based on the expression level of the 8 genes and further require that a decrease in a subject’s immune age value determined in the blood cell sample following exposure to an agent as compared to that in a blood cell sample not exposed to the agent, is indicative that the agent has therapeutic efficacy for treating any immune-related disorder.
Further, the present claims encompass determining the immune age value for a subject based on the expression level of only the 8 genes of ACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4, wherein a decrease in the immune age of the subject is indicative that an agent has therapeutic efficacy for treating any immune-related disorder.
However, the example provided in the specification is limited to a method wherein the mRNA level of a panel of 57 genes was measured in subject’s having Crohn’s disease following treatment with the anti-TNF inhibitor of Infliximab (para [0210]). The panel of genes consisted of: ABLIM1, AFF3, BACH2, BCL11A, BIRC3, BLNK, BTLA, C11orf31, C6orf48, CCR6, CCR7, CD200, CD22, CD27, CD28, CDCA7L, CHMP7, CR2, DPP4, E2F5, EPHX2, FAIM3, FAM102A, FAM134, FCRL1, FCRL2. HOOK1, HVCN1, IL6ST, IMPDH2, KIAA0748, LEF1, LRRN3, MYC, NELL2, NT5E, P2RX5, PAQR8, PLAG1, PTPRK, RCAN3, SCML1, SLC7A6, SNX9, STRBP, SUSD3, TCF4, TCF7, TCL1A, TCTN1, UXT, VPREB3, ZNF101, ZNF671, CRTC3, STAP1 and HLA-DOB (see para [0217]).
The specification does not teach that the mRNA levels of BACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 alone could be used to predict the efficacy of treatment of CD with an anti-TNF inhibitor or the efficacy of treatment with a representative number of diverse agents to treat a representative number of other diverse immune-related disorders. There is no showing that the expression levels of this subset of genes are correlated with immune age or with a particular composition of blood cells, which composition is correlated with immune age.
Moreover, the claims encompass determining the efficacy of an agent to treat a significantly large genus of diverse immune-related disorders. Note that the specification (para [0182]) teaches that “the immune-related disorder is selected from the group consisting of inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, psoriasis, psoriatic arthritis and Behçet's disease.” It is stated (para [0183]) that:
“the immune-related diseases is an autoimmune disease, including, but not limited to cardiovascular diseases, rheumatoid diseases, glandular diseases, gastrointestinal diseases, cutaneous diseases, hepatic diseases, neurological diseases, muscular diseases, nephric diseases, diseases related to reproduction, connective tissue diseases and systemic diseases.”
These disorders vary significantly in their etiology, symptoms and outcomes and there is no clear showing that changes in immune age values, based on the expression level of the 8 gene panel, are correlated with a representative number of these disorders. There is also no showing that the immune age values are predictive of efficacy of a representative number of the diverse types of agents encompassed by the claims for treating a diverse number of the immune-related disorders encompassed by the claims.
As broadly recited, immune-related disorders may also encompass diseases that in any manner involve any aspect of the immune system, such as sepsis, allergies, hives, and any viral, fungal or bacterial infection. However, again, it has not been established that immune age values can be determined based on the expression of the 8 gene panel to predict the responsiveness of a subject to any therapeutic agent to treat these diverse disorders.
Additionally, all results provided in the specification were obtained with human subjects. However, the claims encompass methods which treat and determine the immune age in any subject. Note that the specification (para [0086]) states “The subject who is suffering from the immune-related disorder is a mammal.”
The specification does not teach that the elected combination of 8 genes (or the 57 genes disclosed in the specification) can be predictably used to determine the immune age of a representative number of non-human mammals as indictive of the efficacy of an agent for treating any immune-related disorder in the non-human mammals.
Given the high level of variation in gene expression between different mammals, and the lack of information provided in the specification regarding the expression level of the 8 genes in immune aging in diverse mammalian species, it is unpredictable as to whether the results obtained in human subjects can be extrapolated to a representative number of diverse mammals.
Extensive experimentation would be required to practice the broadly claimed invention given the high level of unpredictability in the art and the significant breadth of the claims.
Case law has established that “(t)o be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation.” In re Wright 990 F.2d 1557, 1561. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) it was determined that “(t)he scope of the claims must bear a reasonable correlation to the scope of enablement provided by the specification to persons of ordinary skill in the art.” The amount of guidance needed to enable the invention is related to the amount of knowledge in the art as well as the predictability in the art. Further, the Court in Genetech Inc. v Novo Nordisk 42 USPQ2d 1001 held that “(I)t is the specification, not the knowledge of one skilled in the art that must supply the novel aspects of the invention in order to constitute adequate enablement."
Additionally, as set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention.
Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
9. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Alpert et al (Nature Medicine. March 2019. 25: 487-495, Supplementary Information and Supplementary Table 14, p. 1-6, 35 pages total) discloses a study which profiled the cellular composition and other immune features of blood samples from 135 healthy subjects, aged 20-31 or 60-96 at enrollment, longitudinally over a 9-year period. It is stated that “We characterized pronounced immune-system dynamics in
older adults that contrasted with the immune-system stability of young adults” (p. 493, col. 2). Alpert (p. 494, col. 1) also states:
“We relied on population-level, longitudinal information of cellular frequencies over short time spans to describe a trajectory approximating a continuum of changes in cell composition that occur over an older adult’s lifetime. This trajectory captures the
individual’s immune-aging process, which we quantified using the IMM-AGE score. The IMM-AGE score is correlated with age, yet it captures additional metrics such as cell-cytokine response better than age. We identified a gene signature approximating IMM
AGE, obviating the need for high-dimensional cytometry data, and used it with data from the Framingham Heart Study to show that IMM-AGE score predicts all-cause mortality, thereby exhibiting a clinically meaningful biological clock.”
Alpert identified 121 genes “whose expression changed significantly (P < 0.05) in >0.6 of the years where they were measured and whose trend in expression along trajectory did not significantly contradict the young-old trend” (p. 3, col. 1 in the Supplementary information). Alpert states that they calculated an IMM-AGE score based on expression levels of 57 of the 121 genes (which genes were used in a Framingham Heart Study; p. 3, col. 1 in the Supplementary information). The 57 genes include each of the BACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 genes, as shown in Supplementary Table 14 of Alpert. Thus Alpert teaches methods comprising measuring the expression of the BACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 genes, together with 49 other genes, in a blood sample from a subject and determining an immune age score for the subject based at least in part on the expression level of the BACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 genes. Alpert also correlated IMM-AGE scores, calculated in part based on gene expression levels of the 57 genes, with overall survival of subjects having cardiovascular disease (i.e., an immune-related disorder).
The prior art of Shen-Orr (WO2019215740; published 14 Nov 2019; cited in the IDS) also teaches methods for calculating an immune age of a subject based in part on the expression level of a panel of 57 genes, which panel includes the ACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 genes (e.g., claims 1 and 11; para [0011], [0019] and [0022]). It is disclosed that the methods therein encompass diagnosing a subject with increased risk of illness, such as cardiovascular disease, when the subject’s immunological agent age is greater than the subject’s chronological age (para [0025-0027]) and that the method may further comprise administering to the subject a prophylactic regimen for the illness (para [0082]).
However, Alpert et al and Shen-Orr et al do not teach or suggest the presently claimed methods of treating an immune related disorder in a subject comprising: (a) contacting blood cells of the subject with the agent; (b) measuring the expression of each of the genes BACH2, BCL11A, CHMP7, DPP4, LRRN3, CD28, EPHX2 and TCF4 in the blood cells; (c) obtaining an immune age value based on the expression of the genes; (d) comparing the immune age value with an immune age value of the subject calculated on the basis of expression of said genes in blood cells of the subject, in the absence of said agent, wherein a decrease in the immune age of the subject is indicative that the agent has therapeutic efficacy for treating the immune-related disorder; and (e) administering the agent to the subject.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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