DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
The information disclosure statement filed 8 November 2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. The deficiency is as follows: the entirety of non-patent literature document 16 is cited by the information disclosure statement, however, only the abstract has been provided. As a result, non-patent literature document 16 has not been considered; however, all other references disclosed have been considered by the Examiner.
The listing of references in the specification 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.
Specification
The use of trade names or marks used in commerce, has been noted in this application (e.g., “NanoDrop” on p11). The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 4, 6, 10, 11, 19, and 24 are objected to because of the following informalities:
Claim 4, line 2: “…subtype.” should be corrected to “…subtype(s).”
Claim 6, line 3: a comma should be placed between “microscopic colitis” and “and from irritable bowel syndrome”.
Claim 10, line 3-4: commas should be placed before and after “..and optionally the level…”
Claim 11: “…and wherein higher amount…” in line 4 should be corrected to “…and wherein a higher amount”; it is also suggested that “…stool sample than in the…” in line 5 should be corrected to “…stool sample [[than in]] as compared to…”
Claim 19, line 2: “…at suitable wavelength.” should be corrected to “…at a suitable wavelength.”
Claim 24: a comma should be placed between “(K8) protein” and “keratin 16” in line 3, and before and after “and calprotectin” in line 5.
Appropriate correction is required.
Claim Interpretation
While the preamble states “determining or confirming chronic inflammatory intestinal disease or risk thereof in a subject…”, the body of the claim recites no diagnostic, distinguishing, or determining step tied to this preamble language. Under MPEP § 2111.02, a preamble is non-limiting where it merely states a purpose or intended use for the invention and the body of the claim is otherwise structurally complete. In the case of the instant claim 1, the steps of the method (i.e., detecting K7 mRNA or protein in a stool sample) can be performed and fully understood independent of the preamble’s recitation of disease determination or confirmation. While the preamble attempts to define the type of subject upon which the method would be performed, it is ineffective in doing so as the subject is not limited solely to those individuals who are suffering from the claimed disease. Therefore, claim 1 can be broadly interpreted as any method in which keratin 7 (K7) mRNA or protein is detected in a stool subject obtained from any subject. Only claims possessing explicit diagnostic or distinguishing steps are limited to the subject of inflammatory intestinal diseases. All other claims are directed towards any method of detecting K7 mRNA/protein.
Multiple “wherein” clauses are present within dependent claims 5, 6, 7, . Under MPEP § 2111.04.I, “wherein” clauses do not automatically limit the scope of the claim and are interpreted in the context of the claim as a whole. Where these clauses simply express the intended result of a positively recited process step, they are not given patentable weight. As such, the scope of these claims is limited only to those limitations which recite process steps.
Regarding claim 16, the recitation of “a stool sample” in line 2 will be interpreted as the same stool sample which is referenced in the preceding claims. Regarding claim 17, any antibody specific to the K7 protein which is immobilized will be interpreted as reading on the instant claim.
Claim Rejections
35 USC § 112(b)
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 11, 12, 16-20 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.
Claim 11 recites the limitation "…the amount of K7 protein…" in lines 2 and 3. There is insufficient antecedent basis for this limitation in the claim. The method of claim 1 detects the presence of K7 protein/mRNA, not the amount of K7 protein/mRNA.
Claim 16 recites the limitation "…a stool sample…" in line 2. It is unclear if this is the same stool sample recited in claims 1, 8, and 9, or if this is a different stool sample entirely.
Claim 17 recites the limitation "…immobilized antibodies…" in line 2. It is unclear if these are the primary antibody, the secondary antibody, or a newly recited third antibody.
Any claim not explicitly rejected above is rejected as a result of its dependency upon a rejected claim.
35 USC § 112(a)
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 6, 7, 11, and 12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112(a), or 35 U.S.C 112 (pre-AIA ), first paragraph, have been described by the court in In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). These factors include, but are not limited to:
(A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP 2164.01(a).
The nature of the invention
These claims are directed towards associating the presence of K7 protein or mRNA with the presence of inflammatory bowel disease (IBD), Crohn’s disease, or ulcerative colitis. Therefore, the nature of the invention is drawn to the art of biological science.
The breadth of the claims
Claim 6 is directed towards distinguishing Crohn’s disease and ulcerative colitis (subtypes of IBD) from microscopic colitis, collagenous colitis (a subtype of microscopic colitis), and irritable bowel syndrome (IBS). Claim 7 is directed towards differentiating between microscopic colitis and IBD. Therefore, both claims 6 and 7 encompass distinguishing between IBD and non-IBD gastroenterological diseases via detecting the presence and/or absence of the K7 protein or mRNA.
Claim 11 is directed towards comparing stool samples of unknown disease state to the stool samples of healthy individuals, wherein more K7 protein or mRNA in the unknown sample as compared to the healthy sample confirms the presence of IBD. Claim 12 is directed towards comparing the amount of K7 protein or mRNA detected in a stool sample of unknown disease state to a cutoff value, wherein a value which is higher than the cutoff indicates the presence, or risk of developing, IBD. Therefore, claims 11 and 12 are directed towards the diagnosis of IBD via detecting the presence and/or absence of the K7 protein or mRNA.
The Unpredictability of the Art and the State of the Prior Art
The art of biology is considered to be unpredictable in that often “an inventor is unable to establish a conception until he or she has reduced to practice the invention through a successful experiment” (Mycogen Plant Science v. Monsanto Co., 243 F. 3d 1316, 1330 (Fed. Cir. 2001)). In order to determine that the presence and/or amount of K7 protein or mRNA can be correlated with a specific disease state (i.e., IBD), experimentation would need to be conducted in which IBD samples are compared to samples from subjects which are healthy or which suffer from alternative diseases. The state of the prior art at the time of the invention was such that the tools for performing such studies were available.
Quantity of Experimentation, Working Examples, and Guidance in the Specification
Figure 1A compares the amount of epithelial cells expressing K7 protein in control samples, ulcerative colitis (UC) samples, Crohn’s disease (CD) samples, collagenous colitis (CC) samples, and lymphocytic colitis (LC) samples. Applicant demonstrates statistically significant differences between control vs UC, control vs CD, UC vs CC, UC vs LC, and CD vs LC; however, no statistically significant difference exists between CD vs CC. Therefore, Applicant’s data demonstrates that substantial overlap in K7 expression between at least certain claimed disease states exists. Accordingly, the instant disclosure does not establish a reliable relationship between K7 expression and the claimed disease states across the full scope of claims, nor provide guidance that would permit a skilled artisan to differentiate between disease states based upon K7 expression data.
The amount of experimentation that would be required to implement the claimed method would go beyond routine optimization as the skilled artisan would first be required to determine if K7 expression is capable of distinguishing between disease states and, if so, establish parameters by which such distinctions can be made.
Additionally, the expression of K7 is not unique to inflammatory intestinal diseases, as evidenced by Fei [Fei F, et al. Journal of Cancer. 2019 Jun 2;10(11):2510-2519]. According to Fei, K7 (or CK7, cytokeratin 7) is expressed in the epithelial cells of the lung and breast but is not expressed by glandular epithelia of the colon and prostate. However, while most colorectal cancers are immunohistochemically negative for K7, in clinical settings some are found to stain positive [p2511]. Fei sought to investigate this phenomenon and found that in 178 cases of colorectal cancer, 71 were positive for K7 expression and they associate that expression with tumor location, differentiation, and lymph node metastasis [p2513]. Therefore, Fei demonstrates the unpredictability of K7 expression as a disease discriminating biomarker.
Level of One of Ordinary Skill in the Art
The level of skill in the art is deemed to be high.
Conclusion
On balance, , the unpredictable nature of the relationship between K7 expression and the claimed disease states, the lack of demonstrated disease-specific separation, and the substantial experimentation that would be required to assess the feasibility of the method outweigh the guidance provided by the disclosure, even assuming a highly skilled artisan with access to the relevant assay techniques, without undue experimentation. Therefore, claims 6, 7, 11 and 12 are not enabled by the instant disclosure.
35 USC § 112(d)
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 20 and 21 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.
Claim 14, from which claims 20 and 21 ultimately depend, recite that the ELISA assay is qualitative. However, claims 20 and 21 are directed towards generating a standard curve and determining the concentration of K7 in a sample and are thus directed to a quantitative determination of analyte concentration, rather than the qualitative positive/negative determination required by claim 14. As a result, claims 20 and 21 are inconsistent with the scope of claim 14 and thus fail to further limit it.
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 § 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 6, 7, 11, and 12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Subject Matter Eligibility Test (see MPEP § 2106):
Step 1: Are the claims directed to a process, machine, manufacture, or composition of matter?
Yes, the claims are directed towards a process.
Step 2A: Are the claims directed to a judicial exception?
Prong 1: Do the claims recite an abstract idea, law of nature, or a natural phenomenon?
Yes, the claims describe a consequence of a natural phenomenon, e.g., the naturally occurring relationship between the presence, absence, or quantity of K7 protein or mRNA in a stool sample and the presence or risk of an inflammatory intestinal disease (i.e., inflammatory bowel disease (IBD) or its subtypes). Specifically:
Claim 6 describes distinguishing these subtypes from collagenous colitis, microscopic colitis, and IBS based upon the presence of K7 alone.
Claim 7 similarly describes differentiating microscopic colitis from IBD based upon the presence of K7 alone.
Claim 11 describes comparing an amount of K7 protein or mRNA detected in a stool sample to the amount detected in a stool sample from a healthy population, wherein a greater amount detected in the questioned sample indicates the presence of IBD.
Claim 12 describes comparing an amount of K7 protein or mRNA detected in a stool sample to a cutoff value determined through the assessment of healthy stool samples, wherein detecting an amount greater than the cutoff value indicates the presence of IBD.
Prong 2: Do the claims recite additional elements that integrate the judicial exception into a practical application?
There are no additional elements which would integrate the judicial exception into a practical application.
Step 2B: Do the claims recite additional elements that amount to significantly more than the judicial exception?
There are no additional elements which would amount to significantly more than the judicial exception.
Therefore, claims 6, 7, 11, and 12 do not contain eligible subject matter.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4, 5, 8-10, 13, 22, and 24 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Chang [US 20170219593 A1].
Regarding claim 1, Chang discloses a method for detecting colorectal cancer or gastrointestinal tract disease in a subject through the detection of CK7 (a.k.a. K7) in isolated circulating tumor cells via cell staining methods [0059]. Circulating tumor cells are isolated from a sample comprised of a body fluid including stool [0149].
In order to isolate the cells, Chang discloses methods for their capture and release. First, a sample comprising the cells is flowed over a surface which is coated with a non-fouling layer comprised of a binding moiety, such as an antibody, that specifically binds to the particle of interest resulting in the capture of the cells. The surface is subsequently washed thereby purifying the sample and various methods are then used to remove the cells from the surface. Once released, the purified cells can be collected and used for downstream processes. In some instances, the binding moiety and the cells are released from the surface together. These collected cells can then be detected and/or counted through a variety of means as depicted in Fig. 24 shown below [0093, 0206-0219, 0230, 0237].
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Regarding claims 4 and 5, the gastrointestinal tract disease which can be detected by this method includes Crohn’s disease and ulcerative colitis [0063].
Regarding claims 8 and 9, cell staining can be performed using antibodies specific for a marker, such as an anti-CK7 antibody. These antibodies may be directly labeled with a fluorescent compound or indirectly labeled using, as an example, a fluorescently-labeled second antibody which recognizes the first antibody [0242].
Regarding claim 10, the isolated cells can be lysed the circulating tumor cells to allow for the identification or enumeration of the genomic DNA, cDNA, or mRNA sequence of specific markers, including CK7 [0238-0241].
Regarding claim 13, the downstream processes which can be conducted using the isolated cells include ELISAs [0219].
Regarding claim 22, cell staining can be followed by flow cytometric analysis to determine the number of stained cells relative to the total number of cells in the population [0244].
Regarding claim 24, Chang teaches the adaptation of their method for multi-marker analysis, allowing for the detection of additional markers including CK20, CK8, CK18, CK19 [0280].
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 14-21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Chang as applied to claims 1, 8, 9, and 13 above, and further in view of Boone [US 20040033537 A1].
Chang is applied to the relevant teachings of claims 1, 8, 9, and 13 as discussed above and is incorporated herein by reference. However, Chang does not teach that the ELISA assay of claim 13 is quantitative or qualitative, the specific steps described by claims 16-21, nor the use of either a lateral flow assay or nuclear magnetic resonance to detect the presence of K7 in a stool sample.
Regarding claims 14 and 15, Boone teaches a qualitative ELISA assay for detecting a protein marker (lactoferrin) in human fecal samples to aid in discriminating between IBD and IBS, as well as a quantitative ELISA assay for determining the level of the protein present in said sample in order to monitor the effects of medical treatments [Boone, abstract, 0014, 0019]. While Boone is directed towards the detection of lactoferrin rather than K7, both are directed towards the clinical evaluation of gastrointestinal disease based upon the presence, absence, or quantity of a protein marker in which this detection and/or quantification is performed via ELISA test. Therefore, a person of ordinary skill in the art prior to the effective filing date of the claimed invention, upon reading Chang’s teaching that ELISA is a suitable downstream detection method, would have recognized the ability of the assay to be conducted in a qualitative or quantitative format as this is demonstrated by Boone. The use of a known technique to improve similar devices (methods or products) in the same way is likely to be obvious. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 – 97 (2007) (see MPEP § 2143, C.).
Regarding claim 16, Boone teaches diluting the fecal sample and establishing an optimal dilution factor in conjunction with the assay’s optical density to achieve accurate, sensitive results [Boone, 0027-0038].
Regarding claim 17, Boone teaches serially diluting fecal specimens. These specimens are added to microtiter wells containing immobilized polyclonal antibodies against human lactoferrin. The samples are incubated resulting in the capture of endogenous lactoferrin by the antibodies [Boone, 0075]. This complex is akin to the treated sample of the instant application.
Regarding claim 18, after incubation of the samples is complete, polyclonal antibodies which are coupled to horseradish peroxidase enzyme is added and allowed to bind the captured lactoferrin creating a readable sample [Boone, 0075].
Regarding claims 19-21, a substrate is added to the readable sample resulting in the development of color. The optical density of the sample is then obtained spectrophotometrically at 450nm. The fecal lactoferrin concentration of the fecal specimens is determined by comparing the optical density results to a standard curve generated using purified human lactoferrin [Boone, 0077].
Regarding claim 23, Boone states that a lateral flow assay may also be used to indicate the absence or presence of gastrointestinal inflammation [0014].
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kara N Kovach whose telephone number is (571)272-8134. The examiner can normally be reached Monday - Friday, 9am - 3pm.
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/K.N.K./ Examiner, Art Unit 1681
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
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