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 without traverse of Group II, methods of determining whether a therapy for a fibrotic, autoimmune and/or inflammatory disease or condition is effective in a subject and the species of the ACVR1C gene and Crohn’s disease in the reply filed on 12 January 2026 is acknowledged. Claim Status 3. Claims 1, 3, 19, 21, 22, 24, 25, 30-39 are pending. Claims 1, 3 , 24, 25, 32, 33 and 35-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention or nonelected species , there being no allowable generic or linking claim. Claims 19, 21, 22, 30, 31 and 34 read on the elected invention and have been examined herein to the extent that the claims read on the elected species of the ACVR1C gene and Crohn’s disease. The claims encompass the non-elected subject matter of methods for screening whether a putative therapeutic agent is effective for treating a fibrotic, autoimmune, and/or inflammatory disease or condition. The claims also encompass the non-elected species of the additionally recited genes and combinations of genes and the addition diseases other than Crohn’s disease. 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. Non-Compliant Amendment 4 . The status identifiers used for claims 32 and 33 are not correct as these claims are directed to non-elected subject matter and should be accompanied by the status identifier of “(Withdrawn) ”. Note that claims 32 and 33 are directed to methods that detect the expression of the non-elected species of the CLCF1. As set forth in MPEP 714, “ For any amendment being filed in response to a restriction or election of species requirement and any subsequent amendment, any claims which are non-elected must have the status identifier (withdrawn). Any non-elected claims which are being amended must have either the status identifier (withdrawn) or (withdrawn – currently amended) and the text of the non-elected claims must be presented with markings to indicate the changes. Any non-elected claims that are being canceled must have the status identifier (canceled). ” MPEP provides the following list of acceptable alternative status identifiers: Objection to Drawings / Objection to the Specification 5. The drawings are objected to under 37 CFR 1.83(a). The specification describes the figures, for example Figure 1A , Figure 2A and 3E in terms of particular colors – i.e. Dark green, blue and red for Figure 1A and yellow ; red and blue for Figure 2A; red and blue for Figure 3E . 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 Objections 6. Claims 30, 31 and 34 are objected to because of the following informalities: Claims 30, 31 and 34 are objected to because the claims recite “ACVR1 C , . ” (see claim 30) whereas the comma after “ACVR1C” should be deleted. Appropriate correction is required. Claims 30, 31 and 34 are also objected because the full terminology for the acronym “HSCT” should be included prior to the first occurrence of the acronym. That is claim 30 should be amended to recite “ hematopoietic stem cell transplant (HSCT) ”. Claim Rejections - 35 USC § 101 7. 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 19, 21, 22, 30, 31 and 34 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 a gene in Figure 2A and particularly the ACVR1C gene and response to therapy for a fi brotic, autoimmune, and/or inflammatory disease or condition . 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 the step of “determining” if a therapy is effective or “predicting” (i.e., is predicted” in claims 30, 31 and 34) if a subject is a good responder. Neither the specification nor the claims set forth a limiting definition for "determining" or “predicting” and the claims do not set forth how “determining” or “predicting” are accomplished. The broadest reasonable interpretation of the “d etermining ” and “predicting” step s is that th e step s may be accomplished by critical thinking processes. Accordingly, these steps constitute an abstract idea / process . The claims also require detecting down-regulation or upregulation of a gene at a second time point as compared to a first time point , as well as detecting an increase in the number of memory B cells, naive B cells, and/or CD8+ T cells or a decrease in the numberer of memory CD4+ T cells, resting CD4+ T cells, and/or naive CD4+ T cells relative to a healthy control (claim 21). The claims necessarily require comparing the amount of expression at the two time points and comparing the number and/or percentage of cells to a healthy control . Note that whether the comparing step is recited as an active step or a passive step, the claims still require that a comparison is mad e . The claims do not set forth how the comparing step is accomplished and the specification does not provide a limiting definition for how the comparing is to be accomplished. As broadly recited, the comparing step may also be accomplished by critical thinking processes. Thereby, the comparing step is also considered to be an abstract idea / process. 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 measuring the expression of a gene in a sample from a subject and quantifying the number or percentage of cells in a sample from a subject (claim 21) are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception. To the extent that the claims require that the subject is one who has been treated with a therapy for a fibrotic, autoimmune, and/or inflammatory disease or condition , the treating is extra-solution activity and is also part of the data gathering step and is not a practical application of the recited judicial exception s . Applicant’s attention is directed to M.P.E.P. § 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 .” Regarding claim 31 and the recitation of “ the subject is treated with hematopoietic stem cell transplant (HSCT) if the subject is determined to be a high expresser of ACVR1C ,” this treating step is conditional and only occurs if the subject is determined to be a high expresser of ACVR1C. The claim includes the embodiment in which the subject is determined to not be a high expresser of ACVR1C and is not administered HSCT. In this embodiment encompassed by the claim, the claim does not recite an additional step which is a practical application of the judicial exception. Further, to any extent that the claims may be amended to recite a final treating step, Applicant’s attention is directed to MPEP 2106.04(d)(2) regarding specific treatments : When determining whether a claim applies or uses a recited judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition, the following factors are relevant. a. The Particularity Or Generality Of The Treatment Or Prophylaxis The treatment or prophylaxis limitation must be "particular," i.e., specifically identified so that it does not encompass all applications of the judicial exception(s). For example, consider a claim that recites mentally analyzing information to identify if a patient has a genotype associated with poor metabolism of beta blocker medications. This falls within the mental process grouping of abstract ideas enumerated in MPEP § 2106.04(a). The claim also recites "administering a lower than normal dosage of a beta blocker medication to a patient identified as having the poor metabolizer genotype." This administration step is particular, and it integrates the mental analysis step into a practical application. Conversely, consider a claim that recites the same abstract idea and "administering a suitable medication to a patient." This administration step is not particular, and is instead merely instructions to "apply" the exception in a generic way. Thus, the administration step does not integrate the mental analysis step into a practical application…. b. Whether The Limitation(s) Have More Than A Nominal Or Insignificant Relationship To The Exception(s) The treatment or prophylaxis limitation must have more than a nominal or insignificant relationship to the exception(s). For example, consider a claim that recites a natural correlation (law of nature) between blood glucose levels over 250 mg/dl and the risk of developing ketoacidosis (a life-threatening medical condition). The claim also recites "treating a patient having a blood glucose level over 250 mg/dl with insulin". Insulin acts to lower blood glucose levels, and administering insulin to a patient will reduce the patient’s blood glucose level, thereby lowering the risk that the patient will develop ketoacidosis. Thus, in the context of this claim, the administration step is significantly related to the recited correlation between high blood glucose levels and the risk of ketoacidosis. Because insulin is also a "particular" treatment, this administration step integrates the law of nature into a practical application. Alternatively, consider a claim that recites the same law of nature and also recites "treating a patient having a blood glucose level over 250 mg/dl with aspirin." Aspirin is not known in the art as a treatment for ketoacidosis or diabetes, although some patients with diabetes may be on aspirin therapy for other medical reasons (e.g., to control pain or inflammation, or to prevent blood clots). In the context of this claim and the recited correlation between high blood glucose levels and the risk of ketoacidosis, administration of aspirin has at best a nominal connection to the law of nature, because aspirin does not treat or prevent ketoacidosis. This step therefore does not apply or use the exception in any meaningful way. Thus, this step of administering aspirin does not integrate the law of nature 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 broadly recited steps of measuring gene expression levels and quantifying the number of cells in a sample were well-known, routine and conventional in the prior art. For example, Corraliza et al (J Crohn’s and Colitis. 06 Dec 2018. 13(5): 634-647 and Supplementary Information, p. 1-18, 32 pages total) teaches methods of assaying a sample from a subject to measure the expression level of ACVR1C in the sample (e.g., section 2.3 beginning at p. 635). Corraliza further teaches conventional methods of flow cytometry for determining the number of B and T cells, including naïve B cells and resting T cells (e.g., abstract; section “3.2” at p.638; and Figure 2). Kim et al ( Experimental Dermatology. 2016. 25: 386-412) teaches methods comprising obtaining a sample from a subject and assaying the sample to measure the expression level of ACVR1C (p. 402 “Experimental design” and Figure 1). Chauchereau et al (U.S. 20130130928A1 ) teaches that methods for measuring gene expression levels were well known in the prior art (e.g., para [0037]) and exemplifies methods for measuring the level of expression of ACVR1C in a sample from a subject (e.g., para [0029] and [0055]). 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. 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. Improper Markush Grouping Rejection 8. Claims 19, 21, 22, 30, 31 and 34 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch , 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi , 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117 . The Markush groupings of the genes in Figure 2A and combinations thereof are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: It is first noted that MPEP 2117 states that “ A Markush claim may be rejected under judicially approved "improper Markush grouping" principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an "improper Markush grouping" if either: (1) the members of the Markush group do not share a "single structural similarity" or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch , 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). “ Members of a Markush group share a “single structural similarity” when they belong to the same recognized physical or chemical class or to the same art-recognized class (prong 1) and the members of a Markush group share a common function or use when they are disclosed in the specification or known in the art to be functionally equivalent (prong 2). The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein “A recognized physical class, a recognized chemical class, or an art-recognized class is a class wherein there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention. In other words, each member could be substituted one for the other, with the expectation that the same intended result would be achieved.” (see MPEP 2117IIA). Herein, the recited alternative species do not share a single structural similarity, as each gene has a different chemical structure in that it consists of a different nucleotide sequence. The only structural similarity present is that all of the genes comprise nucleotides. The fact that the genes comprise nucleotides per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides alone is not essential to the asserted common activity of being correlated with response to treatment for a fibrotic, autoimmune, and/or inflammatory disease or condition. Accordingly, while the different genes are asserted to have the property of having an expression level that correlates with response to treatment for a fibrotic, autoimmune, and/or inflammatory disease or condition, they do not share a substantial structural similarity essential to this activity. Further, the recited genes do not belong to a chemical or art-recognized class because there is no expectation from the knowledge in the prior art that the genes behave in the same manner and can be substituted for one another with the same intended result achieved. There is no evidence of record to establish that it is clear from their very nature that the recited genes possess the common property of having an expression level that is correlated with response to a treatment for a fibrotic, autoimmune, and/or inflammatory disease or condition. Following this analysis, the claims are rejected as containing an improper Markush grouping. To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use. Claim Rejections - 35 USC § 112 (b) - Indefiniteness 9 . 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 19, 21. 22, 30, 31 and 34 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 19, 21.22, 30, 31 and 34 are indefinite over the recitation of the genes in “ Fig. 2A. ” As stated in MPEP 2173.05(s), claims should be complete to themselves and the reference to Figure 2A renders the claims incomplete. Claims which recite figures or tables are only permitted in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into a claim. Claims 19, 21.22, 30, 31 and 34 are indefinite over the recitations of “ the second half of Fig. 2A (genes shown in Fig. 2A (continued)) ” and “ genes listed in the first half of Fig. 2A ” because it is not clear as to what constitutes the “first half” and the “second half” of Figure 2A. To the extent that “the second half of Fig. 2A” is intended to encompass the portion of Fig. 2A that appears on the “continued” page, p arentheticals make the claims indefinite because it is unclear whether the information in the parentheses has the same, less, or more weight as the rest of the claim language . Claims 19, 21.22, 30, 31 and 34 are indefinite over the recitation of “ (e.g., bridging fibrosis) and (e.g., interstitial fibrosis or replacement fibrosis) . The phrase “ e.g. ” / "for example" renders the claims indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claim 21 is indefinite because it is not clear as to whether the claim at (a) requires an additional step of measuring the expression of the gene or intends and if so it is unclear as to the relevance of this step since the claim (as it depends from claim 19) already requires measuring the expression of the gene. Additionally, the claim is confusing over the recitation of a step (a) and (b) since the claim already previously recites a step (a) and (b) since it depends from claim 19. Claims 30, 31 and 34 are indefinite over the recitation of “ The method of predicting whether a subject with a fibrotic, autoimmune, and/or inflammatory disease or condition will respond to a therapy of claim 19 .” This phrase lacks proper antecedent basis since claim 19 is not drawn to a “ method of predicting whether a subject with a fibrotic, autoimmune, and/or inflammatory disease or condition will respond to a therapy .” The claims are also indefinite over the recitation of “a therapy of claim 19” since claim 19 is not drawn to a therapy per se. The claims are further indefinite over the reference to “(b)” since claim 19 already recites a step (b) of “ determining that the therapy or the putative therapeutic agent is effective ”. It is unclear as to whether a second step (b) is to be performed. If a second step (b) is not required, it is unclear as to the relationship between the determining and “is predicted” step. Lastly, it is unclear as to whether “ the expression of ACVR1C is measured in a sample from the subject ” requires an additional step of measuring ACVR1C or if the claim intends to limit the gene that is measured to ACR1C. Claims 30, 31 and 34 are indefinite over the recitation of “if the subject is a high expresser of ACVR1C” because it is not clear as to what constitutes a “high expresser of ACVR1C.” This phrase is not clearly defined in the specification or the claims and there is no art recognized definition for this phrase. “High” is a relative term and the claims do not set forth the criteria for distinguishing between a subject that is a high expresser versus a subject who is not a “high expresser.” It is also unclear as to whether the measuring to determine if the subject is a “high expresser” occurs at the at any point before the start of therapy or at the start of therapy or at any time after the start of therapy . Claim Rejections - 35 USC § 112 (d) / Fourth paragraph 10 . The following is a quotation of 35 U.S.C. 112(d): (d) REFERENCE IN DEPENDENT FORMS.— Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph: Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers. Claims 30, 31 and 34 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. C laims 30, 31 and 34 recite “ The method of predicting whether a subject with a fibrotic, autoimmune, and/or inflammatory disease or condition will respond to a therapy of claim 19 .” T he claims as broadly recited encompass the embodiment in which the claims depend from claim 19 only to the extent that the claims require the “therapy of claim 19 . ” However, claim 19 is not drawn to a therapy per se. T he claims do not require all of the limitations of claim 19 which is drawn to a “ method of determining whether a therapy for a fibrotic, autoimmune, and/or inflammatory disease or condition is effective in a subject or for screening whether a putative therapeutic agent is effective for treating a fibrotic, autoimmune, and/or inflammatory disease or condition .” Accordingly, claims 30, 31 and 343 do not properly depend from claim 19. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Claim Rejections - 35 USC § 112(a) - Enablement 1 1 . 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 19, 21, 22, 30, 31 and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling for methods for determining whether hematopoietic stem cell transplant (HSCT) therapy will be effective at treating systemic sclerosis ( SSc ) in a human subject, the method comprising: a) measuring the level of expression of ACVR1C in a first sample obtained from a human subject having SSc prior to the start of HSCT therapy and in a second sample obtained from the subject after starting the HSCT therapy; and b) determining that the HSCT therapy will be effective for treating scleroderma in the human subject based on the detection of a decrease in the level of expression of ACVR1C in the second sample as compared to the first sample; and for methods for predicting whether a human subject having systemic sclerosis ( SSc ) will respond to hematopoietic stem cell transplant (HSCT) therapy comprising: a) measuring the expression level of ACVR1C in a sample from a human subject having SSc prior to the onset of HSCT therapy ; and b) predicting that the subject will be a good responder to HSCT if the subject has a high expression level of ACVR1C in the sample as compared to a reference median expression level, does not reasonably provide enablement for the broadly claimed methods of determining if any therapy for a f ibrotic, autoimmune, and/or inflammatory disease or condition is effective in a subject having any condition, including the optional conditions recited in claim 19 or for methods for predicting whether a subject with a fibrotic, autoimmune, and/or inflammatory disease or condition will respond to HSCT therapy wherein the method comprises determining at any time point that the subject is a high express or of ACVR1C and predicting that the subject will be a good responder to HSCT if the subject is a higher expresser of ACVR1C. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims. The 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. Claims 19, 21 and 22 are broadly drawn to methods of determining whether a ny therapy for a fibrotic, autoimmune, and/or inflammatory disease or condition is effective in a subject having any disorder based on the detection of a decrease in the level of expression of ACVR1C in a sample obtained from the subject following the therapy as compared to prior to therapy. While the elected species is limited to Crohn’s disease, claim 19 recites that the recited diseases, including Crohn’s disease, are an optional embodiment and thereby the claims encompass detecting the effectiveness of the therapy to treat any disease. Claims 19, 21 and 22 do not define the therapy in terms of any specific structural properties and thereby encompass a significantly large gene of any type of therapy that could be used to treat any fibrotic, autoimmune or inflammatory disease or condition. Claims 30, 31 and 34 encompass methods for predicting if a subject having any fibrotic, autoimmune, and/or inflammatory disease or condition will be responsive to HSCT therapy comprising measuring the expression level of ACVR1C in a sample from the subject at any time point, including after initiating HSCT therapy and predicting that the subject will be a good responder to HSCT therapy if the subject is a higher expresser of ACVR1C. The specification teaches the analysis of changes in gene expression levels over time in blood samples obtained from subjects in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial and particularly in blood samples from patients having systemic sclerosis ( SSc ). The specification teaches that 142 genes were differentially expressed between SSc patients receiving HSCT versus cyclophosphamide (CYC). Regarding the elected species, it is reported that ACVR1C (i.e., “ACV/JC” or “ALK-7”) “ expression was significantly decreased in HSCT treatment compared to the flat trend in CYC (FIG. 2B; P=1.7e-09, FDR=2.6e-05). Similarly, the expression of interleukin-7 receptor (IL7R) dropped in HSCT compared to its expression in CYC (FIG. C; P=7.8e-06, FDR=0.006). ” Regarding claims 30, 31 and 34, the specification further states: “ Patients initially having higher ACVR1C expression had better EFS in HSCT at the end than patients initially having lower expression (P=0.05, HR=0.15, FIG. 4A). Eight of 17 patients with high ACVR1C expression were classified as fibroproliferative (Franks J. M. et al., Arthritis Rheumatol . 2019 October; 71(10): 1701-1710. doi : 10.1002/art.40898. Epub 2019 Sep. 2. [PMID: 30920766]), while only 3 patients with low ACVR1C expression were in this group. This suggest that pre-HSCT expression levels of ACVR1C might be a key determinant for eventual EFS. In contrast, the expression of ACVR1C alone does not predict EFS in the CYC arm (FIG. 4B) .” Regarding additional autoimmune diseases, the specification teaches that the results obtained in studies by Corraliza et al for Crohn’s disease and by Souse et al for MS regarding ACVR1C levels in patients treated with HSCT - see “ Expression of ACVR1C in Other Autoimmune Diseases and HSCT Studies .” It is stated that the data from the CD study and CD4+ CD8+ MS study showed that ACVR1C expression was (initially) decreased with HSCT treatment but was relatively flat over time reflecting the small fold change in expression. It is also stated (para [0153]: “ Neither the CD study nor the MS reported ACVR1C as the differentially expressed genes due to the low fold-changes of the gene (0.86-, 0.83- and 2.2- fold decrease in CD, CD4+ MS, and CD8+ MS respectively). However, in SCOT, ACVR1C had a 3.6-fold decrease between the last time point and baseline. ” The art of determining an association between gene expression levels and a phenotype, such as responsiveness to a therapy to treat a disease, is highly unpredictable. Gene expression may be influenced by a number of factors, in addition to disease itself, and these factors must be considered prior to drawing any conclusions regarding an association between gene expression patterns and prognostic factors associated with response to treatment. One cannot reasonably predict which diseases will necessarily show a change in the level of expression of a gene, and particularly ACVR1C, in response to any treatment for the disease as indicative of the efficacy of the treatment or the responsiveness of a subject to the treatment. The teachings in the specification support this unpredictability. For example, as discussed above, the specification teaches that the prior results obtained with Crohn’s and MS patients do not establish that there is a consistent decrease in the level of ACVR1C in (blood) samples obtained at a last time point and at baseline (para [0154]). Similarly, the specification teaches that the results obtained with one type of therapy are not necessarily predictive of the results that will be obtained with a second type of therapy since the specification teaches that “t he expression of ACVR1C alone does not predict EFS in the CYC arm (FIG. 4B) ” (para [0151]). Further, regarding ACVR1C, the specification (para [0142]) states that “( i ) ts expression was significantly decreased in HSCT treatment compared to the flat trend in CYC (FIG. 2B; P=1.7e-09, FDR=2.6e-05). The unpredictability in the art is also supported by the teachings of Kim et al (Experimental Dermatology. 2016. 25: 386-412). Kim teaches that a decrease in ACVR1C expression “plays a crucial role in the pathogenesis of sensitive skin” (p. 404, col. 1). It is reported that stimulation of the ACVR1C pathway has therapeutic potential in alleviating sensitive skin and reversing pain pathways (p. 403 col. 2 to p . 404 col. 1). Thus, the findings of Kim suggest that a further reduction in the expression level of ACVR1C would not be beneficial (and rather would have a negative effect) on patients suffering from sensitive skin conditions. Extensive experimentation would be required to identify a representative number of additional therapies and diseases in which downregulation of ACVR1C is indicative of the effectiveness of the therapy or in which a high level of expression of ACVR1C (at baseline or during or after therapy) is predictive of a subject’s responsiveness to the therapy. 35 USC 112 (a) / first paragraph requires that the invention is enabled at the time the invention is made. "[T]o be enabling, the specification.. , must teach those skilled in the art how to make and use the full scope of the claimed invention without 'undue experimentation.'" Wright, 999 F.2d at 1561, 27 USPQ2d at 1513 (emphasis added), quoted in Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1365, 42 USPQ2 1001, 1004 (Fed. Cir. 1997). Thus, "there must be sufficient disclosure, either through illustrative examples or terminology, to teach those of ordinary skill how to make and how to use the invention as broadly as it is claimed." In re Vaeck , 947 F.2d 488, 496 & n. 23, 20 USPQ2d 1438, 1445 & n. 23 (Fed. Cir. 1991), quoted in Enzo Biochem , Inc. v. Calgene , Inc., 188 F.3d 1362, 1372, 52 USPQ2d 1129, 1138 (Fed. Cir. 1999). Thus, while methods for expression profiling were known in the prior art, such methods provide only the general guidelines that allow researchers to search for mRNAs whose expression patterns may linked to the responsiveness to a particular therapy in a particular disease or condition. The results of performing such methodology are highly unpredictable. The specification has provided only an invitation to experiment. A s 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. Priority 12. The present claims are entitled to priority to provisional application 63/089,207, filed 08 October 2020. Claim Rejections - 35 USC § 10 2 1 3 . 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. 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) 19 and 22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Aziz et al (WO2008082730A2) . Aziz teaches methods comprising: measuring the expression level of ACVR1C in a sample from a subject obtained at a time point before starting Raf kinase inhibitor therapy (i.e., baseline) and after starting therapy and determining that the therapy is effective if the expression level of ACVR1C is decreased in the sample obtained after starting therapy a s compared to the expression level at baseline (see Table VII, entry #6554; p. 6, lines 1-15, and p. 294, line 13 to p . 295, line 6). The reference states “Table VII is a subset showing the biomarkers of Table I that are preferred according to a different aspect of the invention because they showed significant alterations in expression level compared to baseline sustained over several time points.” Further, Aziz teaches that the Raf kinase inhibitor is for the treatment of cancer / a cell proliferative disorder (e.g., p. 5, line 24-25; and p. 14, lines 3-7 ) , which is a disease associated with inflammation. Thereby, the method of Aziz is one for determining if a therapy for an inflammatory disease is effective. Note that in claim 19, the identity of the disorder or condition is optional and the claim is not limited to the elected disorder of Crohn’s disease. Regarding claim 22, Aziz teaches that the sample is a blood sample (e.g., p. 296, lines 4-12). Claim Rejections - 35 USC § 103 14. 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. This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention. Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Aziz et al (WO2008082730A2) in view of Callahan et al (Cancer Immunol Res. 2014. 2(1), p. 1-17). The teachings of Aziz are presented above. Aziz does not teach that the method further comprises quantifying the number of CD8+ T cells and determining that the therapy is effective if the number of CD8+ T cells increases as compared to a healthy control. However, Callahan teaches that treatment with the RAF inhibitor of BMS908662 leads to activation of, and an increase in the number of, CD8+ T cells, as compared to untreated subjects (e.g., p. 4 and “B MS908662 potentiates T cell activation in vitro ”). It is stated that “