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 .
This Office Action is in reply to Applicants’ correspondence of 04/15/2026.
Applicants’ remarks and amendments have been fully and carefully considered but are not found to be sufficient to put the application in condition for allowance. Any new grounds of rejection presented in this Office Action are necessitated by Applicants’ amendments. Any rejections or objections not reiterated herein have been withdrawn in light of the amendments to the claims or as discussed in this Office Action.
This Action is made FINAL.
Please Note: The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Election/Restrictions
In the reply filed on 11/07/2025 Applicants elected, without traverse, the particular species that are: the gene WFDC1; the analyte that is protein; and the pathology that is a dermatological disorder, is acknowledged.
In light of the Examiner’s search and analysis of the elected species that is the analyte ‘protein’, the species election requirement between mRNA and protein (p.2 of the Requirement of 09/11/2025) was withdrawn.
In light of the Examiner’s search and analysis of the elected species that is a ‘dermatological disorder’, the species election requirement between dermatological disorder and hyper-proliferative disorder (p.2 of the Requirement of 09/11/2025) was withdrawn.
Claim 2 remains withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected combination of species (i.e.: requiring at least two of the six recited genes from claim 1, where the election is the single gene that is WFDC1), there being no allowable generic or linking claim.
Election was made without traverse in the reply filed on 11/07/2025.
Withdrawn Claim Objections
The objections to claims 1 and 19, as set forth on page 3 of the Office Action of 02/12/2026, are withdrawn in light of the amendments to the claims.
.
Maintained Objection to the Drawings – Color Drawings, Figures, Pictures
The objection to the drawings for containing drawings executed in color, as set forth on pages 3-4 of the Office Action of 02/12/2023, is maintained. It is noted that the reply of 04/15/2026 includes a petition under 37 CFR 1.84(a)(2) to file color drawings, but that petition has not yet been reviewed. The results of the petition decision will be provided in a separate correspondence.
Maintained Objection to the Specification
The objection to the disclosure for making reference to colors in the drawings, as set forth on page 4 of the Office Action of 02/12/2023, is maintained. It is noted that the reply of 04/15/2026 includes a petition under 37 CFR 1.84(a)(2) to file color drawings, but that petition has not yet been reviewed. The results of the petition decision will be provided in a separate correspondence.
Withdrawn Claim Rejections - 35 USC § 112 - Indefiniteness
The rejections of claims under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as set forth on page 5 of the Office Action of 02/12/2023, are withdraw in light of the amendments to the claims.
New Claim Rejections - 35 USC § 112 – Indefiniteness
Necessitated by Claim Amendments
Claims 3-7,9-10,12-16,19 and 21 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 3-7,9-10,12-16,19 and 21 are unclear over recitation of the limitation “the expression level of the one or more genes”, as recited in independent claim 19 from which claims 3-7,9-10,12-16, and 21 depend. The limitation is unclear because there is no antecedent basis for any “genes”; note that claim 19 is amended to remove recitation of “genes” in part (a) of the claim (i.e.: determination of a biomarkers selected).
Claim Rejection - Improper Markush Group
Maintained/Newly Applied as Necessitated by Claim Amendments
Claims 3-7,9-10,12-16,19 and 21 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(II).
The Markush grouping of:
one or more genes biomarkers selected from a protein marker or an mRNA biomarker…
wherein the protein biomarker is selected from melanoma cell adhesion molecule (MCAM) having SEQ ID NO. 1, WAP four-disulfide core domain 1 (WFDC1) having SEQ ID NO. 2, insulin like growth factor 1 (IGF1) having SEQ ID NO. 3, insulin like growth factor binding protein 2 (IGFBP2) having SEQ ID NO. 4, transcriptional coactivator and phosphatase 4 (EYA4) having SEQ ID NO. 5, and RNA binding motif protein 24 (RBM24) having SEQ ID NO. 6; and
wherein the mRNA biomarker is selected from MCAM having SEQ ID NO. 7, WFDC1 having SEQ ID NO. 8, IGF1 having SEQ ID NO. 9, IGFBP2 having SEQ ID NO. 10, EYA4 having SEQ ID NO. 11, and RBM24 having SEQ ID NO. 12;
As recited in the claims, is 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(II) 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 “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 2117(II)).
Herein, the recited alternative species do not share a single structural similarity, as each different biomarker (i.e.: the different genes, mRNAs, proteins) has a different chemical structure in that it consists of a different nucleotide, or amino acid, sequence. The only structural similarity present is that all of the genes and mRNAs comprise nucleotides, and the different proteins comprise amino acids. The fact that the biomarkers comprise nucleotides, or amino acids, per se does not support a conclusion that they have a common single structural similarity because the structure of comprising nucleotides, or amino acids, alone is not essential to the asserted common activity of being correlated with the response to steroid treatment. Accordingly, while the different biomarkers are asserted to have the property of being correlated with response to steroid treatment, they do not share a substantial structural similarity essential to this activity.
Further, there is no expectation from the knowledge in the prior art that mRNAs or proteins 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 biomarkers possess the common property of being correlated with response to steroid treatment.
Following this analysis, the claims are rejected as containing an improper Markush grouping.
Response to Remarks
Applicants have transversed the rejection of claims as directed to an improper Markush style grouping of alternatively useable elements. Applicants’ arguments (p.7-9 of the Remarks of 04/15/2026) have been fully considered but are not found to be persuasive. Applicants have argued that the claims do not require that all mRNA or all protein s behave in the same manner (e.g.: with regard to predicting response to steroid treatment), but only that the subset for species as recited in the claims behave in the required manner. This argument is not persuasive because neither the specification nor the related art present the particular recited elements (i.e.: MCAM, WFDC1, IGF1, IGFBP2, EYA4, and RBM24) as defining an “art-recognized class”. The Examiner maintains that the species of the claims belong to the art-recognized classes that are proteins and mRNA, but that these classes art not understood to necessarily have the functionality of being associated with response to steroid treatment.
Applicants have next argued that rejection requires that the different elements of the Markush group have a single structural similarity at the granularity of nucleotide (in the case of mRNA biomarker) or amino acid (in the case of protein biomarkers) sequence level. This argument is not persuasive because the rejection does not make any such requirement. The rejection merely points out that the different elements are each unique biomolecules which do not in fact share any structural similarity that is mainly responsible for their functionality in the claimed methods. While Applicants have pointed to board decisions (i.e.: In re Buyyarapu, Appeal No. 2018-006665; In re Zeigerson, Appeal No. 2017-998749) to support the argument that the alternative elements represent a proper Markush group, the Examiner maintains that the facts of the instant case are more similar to the affirmed rejections of an improper Markush group as provided in Ex parte Chettier (Appeal 2016-003639) and Ex parte O’Brien (Appeal 2025-003266).
Claim Rejections - 35 USC § 101
Maintained/Newly Applied as Necessitated by Claim Amendments
Claims 3-7, 9-10,1 2-16, 19 and 21 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exceptions including abstract ideas and natural phenomena without significantly more.
The claim(s) recite(s) methods of: identifying the steroid sensitive phenotype or steroid resistant phenotype (claim 19). The claims are directed to an evaluation of data or information to reach a conclusion or make a judgment, which is a mental process that is an abstract idea (see MPEP 2106.04(a) III). Additionally, where claims recite a correlation between biomarker expression and the response or non-response to steroid treatment, the claims are directed to the natural association between gene expression and phenotype, and thus is directed to a natural phenomenon (see MPEP 2106.04(b) I).
This judicial exception is not integrated into a practical application because the claims do not practically apply the judicial exception(s), as noted above, by including one or more additional elements that the courts have stated integrate the exception into a practical application:
An additional element reflects an improvement in the functioning of a computer, or an improvement to other technology or technical field;
An additional element that applies or uses a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition;
An additional element implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim;
An additional element effects a transformation or reduction of a particular article to a different state or thing; and
An additional element applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception.
Claim 19 is directed to a “method for treating”, where the relevant treatment step is recited as:
(b) treating the individual classified as having a steroid sensitive phenotype with a steroid that is suitable for the condition, or treating the individual classified as having a steroid resistant phenotype with a non-steroidal treatment that is suitable for treatment of the condition
When evaluating if the claims integrate any judicial exception(s) into a practical application, the particularity or generality of the treatment is considered (see MPEP 2106.04(d)(2)(a)). Here it is noted that where the claims encompass “treating the individual … with a non-steroidal treatment that is suitable for treatment of the condition”, the required treatment is not recited with any particular specificity of what is included, and is only limited by recitation of “a non-steroidal treatment”. The breadth of the treatment is not even limited to alleviation of any particular pathology, and encompass treatment of any condition with a suitable treatment. Such a limitation is not sufficient to integrate the judicial exception(s) of the claims into a practical application sufficient to create patent eligible subject matter. The instant case is similar to the example of MPEP 2106.04(d)(2)(a)):
… 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.
Here it is noted that while some of the claims broadly recite steps of detecting an mRNA or protein biomarker in a sample, these steps are not considered to integrate the judicial exception(s) into a practical application because they merely add insignificant extra-solution activity (data gathering) to the judicial exception (see MPEP 2106.05(g)).
The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s) because a step of detecting expression of a biomarker in in a sample is well understood, routine and convention activity in the related prior art. The routine nature of the additional elements is taught by the disclosure as filed. For example, the specification teaches the following:
p.23 - One or more samples may be obtained from a subject by techniques known in the art, such as biopsy. The type of biopsy utilized is dependent upon the anatomical location from which the sample is to be obtained. Methods for collecting various body samples are known in the art.
p.29 - Antibodies specifically reactive with the antigens of protein biomarkers disclosed herein or derivatives, such as enzyme conjugates or labeled derivatives, may be used to the detect antigens in various samples, for example they may be used in any known immunoassays which rely on the binding interaction between an antigenic determinant of a protein and the antibodies. Examples of such assays are radioimmunoassays, enzyme immunoassay (e.g., ELISA), immunofluorescence, immunoprecipitation, latex agglutination, hemagglutination, and histochemical tests.
p.36 - The presence of antigen in a sample from a subject may be determined by nucleic acid hybridization, such as but not limited to Northern blot analysis, dot blotting, Southern blot analysis, fluorescence in situ hybridization (FISH), and PCR. Chromatography, preferably HPLC, and other known assays may also be used to determine messenger RNA levels of antigens in a sample.
The prior art also demonstrates the well understood, routine, conventional nature of additional elements because it teaches that the additional elements are well known. For example, Javad et al (2012) teaches proteomic analysis of keloid scar tissue, Chen et al (2003) teaches a whole transcriptome analysis of keloid and normal tissue, Seifert et al (2008) teaches a whole transcriptome analysis of keloid lesions, and McAlhany et al (2003) teaches methods that include the detection of WFDC1 (also known as ps20) mRNA and protein in samples.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 101 as directed to subject matter that is not significantly more than a judicial exception recited in the claims. Applicants’ arguments (p.9-10 of the Remarks of 04/15/2026) have been fully considered but are not found to be persuasive. Applicants have argued that the amended claims have removed the option of withholding treatment from a subject. This argument is not persuasive. As set forth in the rejection, the recited “treating the individual … with a non-steroidal treatment that is suitable for treatment of the condition” is recited at a high level of generality and is not sufficient to provide an integration of the judicial exceptions into a practical application that creates a claim that is significantly more than the recited judicial exception(s).
Claim Rejections - 35 USC § 112 – Scope of Enablement
Maintained/Newly Applied as Necessitated by Claim Amendments
Claims 3-7, 9-10,1 2-16, 19 and 21 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 (as consonant with the Election):
A method for determining whether or not a keloid lesion from a human subject will respond to treatment with triamcinolone acetonide, the method comprising:
(a) providing a sample from the subject, the sample comprising keloid fibroblasts from a keloid lesion that has been treated with triamcinolone acetonide;
(b) detecting the level of WFDC1 (WAP Four-Disulfide Core Domain 1) mRNA in the keloid fibroblasts from the sample;
(c) comparing the level of WFDC1 mRNA in the keloid fibroblasts of the sample to a control level, where the control level is the level WFDC1 mRNA in keloid fibroblasts from a keloid lesion that has not been treated with triamcinolone acetonide;
wherein a higher level of WFDC1 mRNA expression in the treated fibroblasts as compared to the untreated fibroblasts is detected, and the keloid lesion from the subject is determined to be sensitive and therefore responsive to treatment with triamcinolone acetonide; or a lower level of WFDC1 mRNA expression in the treated fibroblasts as compared to the untreated fibroblasts is detected, and the keloid lesion from the subject is determined to be resistant and therefore non-responsive to treatment with triamcinolone acetonide
does not reasonably provide enablement for the claims as broadly written. 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/or use the invention commensurate in scope with these claims.
Scope of the Claims/Nature of the Invention
The claims the detection of WFDC1 expression levels of any analyte (e.g.: mRNA or protein) from any sample type (e.g.: tissue; body fluid; cells) from a human subject organism for determining responsiveness to any steroid treatment by comparison of the expression level reference levels.
The claimed methods thus require knowledge of a reliable relationship to a variety of measured expression values in different sample types from different subject organisms and a response to different types of steroids.
Teachings in the Specification and Examples
The specification (p.50) teaches an example of the analysis of RNA gene expression levels in keloid fibroblasts from keloid lesions from human subjects before and after treatment with triamcinolone acetonide (TA) (p.54 – Example 2). The specification teaches (relevant to the Election), that WAP Four-Disulfide Core Domain 1 (WFDC 1 ) is upregulated in steroid resistant keloid fibroblasts.
The specification does not teach any comparison of WFDC1 gene expression other than mRNA in keloid fibroblasts before and after treatment with TA.
State of the Art and the Unpredictability of the Art
While methods of measuring gene expression are known in the art, methods of correlating the level of gene expression with a phenotype (i.e.: the response or non-response to steroid treatment) are highly unpredictable.
Because the claims encompass examining any sample types (e.g.: whole blood, serum, plasma, saliva, urine, as recited on p.42 of the specification), while the specification teaches only an analysis of fibroblasts from keloid lesions, it is relevant to point out the unpredictability with regard to the analysis of gene expression profiles obtained from different sample types. Cobb et al (2002) teaches the analysis of gene expression in spleen and liver samples from septic mice. Notably, the reference teaches that, when compared to a non-septic sample, the relevant expression profiles of the septic mouse spleen and the septic mouse liver contain different nucleic acids at different levels (Table 1; p.2714, middle col., lns.2-8). It is thus unpredictable as to how one might extrapolate gene expression levels from a keloid fibroblast sample (as provided in the instant specification) to the analysis of gene expression in a sample obtained from any other source.
The specification teaches only a diagnostically relevant comparison of treated and untreated keloid fibroblasts. Because the claims broadly and generically encompass a comparison of gene expression with any “reference expression level”, it is relevant to point out that the prior art of Cheung et al (2003) teaches that there is natural variation in gene expression; so it is unpredictable if any comparison to any reference, as generically encompassed by the claims are indicative of treatment response.
Because the claims encompass the analysis of any gene expression biomarker analytes (e.g.: protein or mRNA), whereas the specification provides only the example of mRNA analysis of WFDC1 (as consonant with the Election), it is relevant to point out that Chen (2002) teaches that it is common for protein expression to be discordant with mRNA expression levels even in matched samples (e.g.: Figure 3). Thus, it is unpredictable as to how to extrapolate the mRNA-based teachings of the instant specification to the analysis of any other different analyte.
Because the claims encompass determining responsiveness to treatment with any steroid (see for example page 44 of the Specification), but only provide an example of treatment with triamcinolone acetonide (TA), it is relevant to point out the breadth of the claim in this regard. The instant specification teaches that there are in fact several distinct classes of steroids based on chemical structure (see for example page 13 of the Specification). And Darbre et al (1987) teaches that different steroids can affect the same type of cell in different ways, which may include differences in affected gene expression levels in the cells or tissue. As such it is unpredictable whether or not the biomarkers that are relevant to TA treatment would be relevant to treatment with any other different steroid.
Quantity of Experimentation
The quantity of experimentation necessary to make and use the invention in the full scope as claimed is great, on the order of many man-years, and then with little if any reasonable expectation of successfully enabling the full scope of the claims. The experimentation would require case:control analysis of any levels of WFDC1 mRNA or protein in any samples as compared to any reference to determine responsiveness to any steroid treatment. Even if such extensive experimentation were to be performed, there is no indication that any associations, beyond those particular associations disclosed in the specification, would be found.
Conclusion
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.
Response to Remarks
Applicants have traversed the rejection of claims under 35 USC 112 as encompassing non-enabled subject matter. Applicants’ arguments (p.10 of the Remarks of 04/15/2026) have been fully considered but are not found to be persuasive. Applicants have argued that:
… the claims has been clarified to be a human. The sample type has been limited to keloids and surgical biopsies (which can include keloid tissue), which may be cell samples, wherein the cells are abnormal or diseased. The condition has been limited to a hyper-proliferative disorder or a dermatological disorder, both categories under which keloid falls.
The argument is not persuasive because while claim 19 (i.e.: the independent claim) is amended to recite a human individual, the amended claim does not in fact address the particular sample types (keloids), analytes (mRNAs), reference samples (treated cells) or particular steroids (triamcinolone acetonide). Applicants arguments point to Example to of the specification as enabling support for the breadth of the methods as claimed. However it is noted that Example 2 specifies that:
To understand the underlying molecular mechanisms of differential steroid
sensitivity in keloids, the inventors identified DEGs in steroid sensitive and resistant keloid 10 fibroblasts following steroid treatment . A total of 526 genes are upregulated and 521 genes were downregulated in steroid sensitive keloid fibroblasts after TA treatment…
The Examiner maintains that in light of the evidence provided in the rejection pertaining to the unpredictability associated with the breadth of the elements of the claims, the claims encompass subject matter that would require undue experimentation by the skilled artisan to make and use the methods in the full scope as claimed.
Withdrawn Claim Rejections - 35 USC § 102
The rejection of claims made under 35 U.S.C. 102(a)(1) as being anticipated by Madar et al (2009), as set forth on pages 16-17 of the Office Action of 02/12/2026, is withdrawn in light of the amendments to the claims.
Conclusion
No claim is allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHEN THOMAS KAPUSHOC whose telephone number is (571)272-3312. The examiner can normally be reached M-F, 8am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Anne Gussow can be reached at 571-272-6047. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683
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