Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election without traverse of the particular species that are: the gene WFDC1; the analyte that is protein; and the pathology that is a dermatological disorder, in the reply filed on 11/07/2025 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analyte ‘protein’, the species election requirement between mRNA and protein (p.2 of the Requirement of 09/11/2025) is withdrawn; claim 3, indicated as ‘withdrawn’ in Applicants’ reply of 11/07/2025 is examined.
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requirement between dermatological disorder and hyper-proliferative disorder (p.2 of the Requirement of 09/11/2025) is withdrawn.
Claim 2 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected combination of species (i.e.: requiring at least two of the six recited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.
Information Disclosure Statement
The listing of references in the specification, see pages 55-57 of the specification as filed, is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
Claims 1 and 19 are objected to because of the following informalities:
Claim 1 is objected to over recitation of the gene symbol WFDC1, where at the first instance of the gene symbol in the claims the symbol should be accompanied by the full gene name consonant with the teachings of the specification. For example: WFDC1 (WAP Four-Disulfide Core Domain 1).
Claim 19 is objected to over the recitation of the term “oof” in line 10, where the term “of” is likely intended.
Appropriate corrections are required.
Objection to the Drawings – Color Drawings, Figures, Pictures
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition 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 the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, 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. See Figs 1A, 1B, 1C, 2A, 2B and 3B of the Drawings. 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).
Specification
The disclosure is objected to because of the following informalities:
The specification contains references to different colors in the drawings (see the description of Figures 1A-1C on page 6: Red color denotes higher mean expression levels and blue color denotes lower mean expression levels…). Please note that if the current drawings are replaced with black and white drawings (see objection to the drawings as set forth above in this Office Action), then the description of the drawings should be amended to remove reference to colors.
Appropriate corrections are required if the current drawings are replaced.
Claim Rejections - 35 USC § 112 - Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 3-20 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 1 and 3-20 are unclear over recitation of the phrase “an expression level of … WFDC1 (SEQ ID NO. 8)”, as recited in claims 1 and 19 and relevant to the Election. Where “SEQ ID NO: 8” is recited as a parenthetical expression, it is unclear if the claims are intended to require the sequence as set forth in SEQ ID NO: 8, or if SEQ ID NO: 8 is merely an exemplary sequence of what may be encompass by the determination of the claims but is not required. The claims are further unclear in this regard where the relevant step is the determination of an expressed analyte, but the recited sequence is a genomic fragment that appears to include sequences that are neither transcribed nor translated.
Claims 17 and 18 are unclear over recitation of the phrase “receiving results of the method of claim 1”, as recited in claim 17 from which claim 18 depends, because there is no antecedent basis for any “results” from the method of claim 1.
Claim Rejection - Improper Markush Group
Claims 1 and 3-20 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 selected from among MCAM (SEQ ID NO. 7), WFDC1 (SEQ ID NO. 8), IGF1 (SEQ ID NO. 9), IGFBP2 (SEQ ID NO. 10), EYA4 (SEQ ID NO. 11), and RBM24 (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.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, and 3-20 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: determining whether or not an individual will respond to a steroid therapy (claim 1); selecting a therapy (claim 17); and 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 17 is directed to “selecting a therapy”, which as noted above is only an identification (i.e.: an abstract idea) of a treatment, not any requirement that a treatment is in fact administered. And claim 19 is directed to a “method for treating”, but encompasses methods in which treatment is withheld, thus encompassing methods in which no treatment is applied or administered (see MPEP 2106.04(d)(2))
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.
Claim Rejections - 35 USC § 112 – Scope of Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3-20 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 any subject organism for determining responsiveness to any steroid treatment by comparison of the expression level to any reference.
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 the analysis of any non-human samples.
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 specification asserts that the methods are applicable to any subject organism (e.g.: specification at page 44), but teaches only the analysis of human samples, it is relevant to point out that it is highly unpredictable as to whether the results obtained in human subjects could be extrapolated to non-human subjects. Hoshikawa et al (2003) teaches unpredictability with regard to applying gene expression results among different organisms. The reference teaches the analysis of gene expression in lung tissue in response to hypoxic conditions which lead to pulmonary hypertension (Fig. 1). The reference teaches that the gene expression profile in mouse is different from that observed in rat (Tables 1-4; p.209 -Abstract). Thus, it is unpredictable as to whether or any genes that steroid response-related in humans are in fact applicable to diagnosing steroid responsiveness in any other non-human organism.
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 form any subjects 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.
Claim Rejections - 35 USC § 102
It is noted that the claims have been previously rejected in this Office Action under 35 USC 112(a) for issues related to enablement with regard to the intended use of the methods in determining responsiveness to steroid treatment. Here the claims are rejected insofar as they require only a practical step of “determining an expression level” (as recited in claim 1). Where claim 1 recites several “wherein” clauses related to compared expression levels as they may be associated with responsiveness to steroid treatment, these clauses are not required practical steps of the claims, but only asserted properties of compared expression levels related to the intended use of the methods.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 3, 5, 6, 7, 9, 10, 12, 13, 14, 15, 16 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Madar et al (2009)
Relevant to the rejected claims, Madar et al teaches the detection of the expression levels of WFDC1 (claim 1) mRNA (claim 3) using QRT-PCR (claims 5 and 6) applied to fibrosarcoma samples (claims 9, 10, 12, 13, 16), (e.g.: p.21 – Sarcoma samples; Fig. 2B).
Relevant to the rejection of claim 7, 14, and 15, the limitations of the rejected claims are directed to the intended use of the method, and do not include any additional practical steps that distinguish the claimed methods from the methods of the cited prior art.
Conclusion
No claim is allowed.
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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Stephen Kapushoc
Primary Examiner
Art Unit 1683
/STEPHEN T KAPUSHOC/Primary Examiner, Art Unit 1683