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
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
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 11 and 14 are rejected under 35 U.S.C. 101 because they constitute abstract ideas and laws of nature.
Regarding independent claim 11, a two-step analysis is performed:Step 1: Does the claim fall within a statutory category?
Yes, it is a method/process.
Step 2A, Prong 1: Identify the law of nature/natural phenomenon/abstract ideas.
A method of differentiating hepatocytes with bile ductular proliferation from hepatocytes without bile ductular proliferation which comprises the step of: detecting laminin γ2 single chain or a nucleic acid encoding the same in a specimen, wherein in a case where laminin γ2 single chain or a nucleic acid encoding the same is detected, the specimen is determined to contain hepatocytes with bile ductular proliferation, and in a case where laminin γ2 single chain or a nucleic acid encoding the same is not detected, the specimen is determined not to contain hepatocytes with bile ductular proliferation.
Determining whether a specimen having laminin γ2 is indicative of hepatocytes with bile ductular proliferation is considered a mental process, where it is evaluated based on one’s observation, evaluation, judgment and opinion using data as comparison, making this an abstract idea. Furthermore, laminin γ2 is a naturally occurring product in hepatocytes with bile ductular proliferation, and is considered a law of nature.
Step 2A Prong 2: Has the abstract idea been integrated into a particular practical application?
The claim as a whole does not integrate the abstract idea or law of nature into a practical application. Other than the abstract idea and law of nature, claim 11 recites the additional element: detecting laminin γ2 single chain or a nucleic acid encoding the same in a specimen. With respect to mentioned additional elements, they represent insignificant extra solution activity (e.g., mere data gathering). Thus, there is no application of the abstract idea or law of nature, much less a particular practical application.
Step 2B: Does the claim recite any elements which are significantly more than the abstract idea?
Claim 11 does not provide an inventive concept (significantly more than the abstract idea or law of nature). Detecting laminin γ2 single chain or a nucleic acid encoding the same in a specimen is considered insignificant extra solution activity (e.g., mere data gathering). Furthermore, the additional element above is well understood, routine, and conventional activities within the prior art (see 102 rejection).
Regarding independent claim 14, a two-step analysis is performed:Step 1: Does the claim fall within a statutory category?
Yes, it is a composition.
Step 2A, Prong 1: Identify the law of nature/natural phenomenon/abstract ideas.
A biomarker for detecting hepatocytes with bile ductular proliferation, comprising: laminin γ2 single chain or a nucleic acid encoding the same.
Laminin γ2 is a naturally occurring product in hepatocytes with bile ductular proliferation and other liver diseases/conditions, and is considered a law of nature.
Step 2A Prong 2: Has the abstract idea been integrated into a particular practical application?
The claim as a whole does not integrate the abstract idea or law of nature into a practical application. Claim 14 does not recite any additional elements that would integrate laminin γ2 into an application of the law of nature, much less a particular practical application.
Step 2B: Does the claim recite any elements which are significantly more than the abstract idea?
Claim 14 does not provide an inventive concept (significantly more than the law of nature). Laminin γ2 is well understood biomarker used within the prior art (see 102 rejection).
Claim Rejections - 35 USC § 102
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.
Claims 1-5, 9 and 14-18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ryu et al. ("Differential TM4SF5-mediated SIRT1 modulation and metabolic signaling in nonalcoholic steatohepatitis progression", as cited in the IDS).
Regarding claim 1, Ryu et al. teaches a method of detecting a biomarker for detecting hepatocytes with bile ductular proliferation which comprises the step of: detecting laminin γ2 single chain or a nucleic acid encoding the same as the biomarker in a specimen (see pg. 55/Abstract, pg. 59/Older TM4SF5-transgenic mice show NASH with progressive fibrosis, pg. 66/Discussion, disclosing laminin γ2 expression in liver fibrosis development, where immunohistochemical studies reveal overexpression of collagen I and laminin γ2 in tetraspanin transmembrane 4 L six family member 5 (TM4SF5, involved in hepatic fibrosis and cancer) mice as compared to wild type mice. Additionally, Immunostaining for laminin γ2 in the cytoplasm of hepatic carcinoma cells has been reported at the invasive front and laminin γ2 has been reported to be a novel serum biomarker for HCC. Thus, laminin γ2 and collagen I α1 may be promising targets for preventing precancerous liver disease and hepatic cirrhosis (advanced stage hepatic fibrosis).).
Regarding claim 2, Ryu et al. teaches wherein hepatocytes with bile ductular proliferation are cells having a liver disease causing bile ductular proliferation (see pg. 55/Abstract, pg. 59/Older TM4SF5-transgenic mice show NASH with progressive fibrosis, disclosing laminin γ2 expression in liver fibrosis development, where immunohistochemical studies reveal overexpression of collagen I and laminin γ2 in tetraspanin transmembrane 4 L six family member 5 mice as compared to wild type mice. It is stated that tetraspanin transmembrane 4 L six family member 5 is particularly involved in hepatic fibrosis development, a disease known in the art for causing ductular reactions).
Regarding claim 3, Ryu et al. teaches the method according to claim 2, wherein the liver disease causing bile ductular proliferation is selected from the group consisting of primary biliary cholangitis, acute hepatitis, fulminant hepatitis, liver failure, primary sclerosing cholangitis, hepatic fibrosis, biliary atresia, and cholestasis (see pg. 55/Abstract, pg. 59/Older TM4SF5-transgenic mice show NASH with progressive fibrosis, disclosing laminin γ2 expression in liver fibrosis development, where immunohistochemical studies reveal overexpression of collagen I and laminin γ2 in tetraspanin transmembrane 4 L six family member 5 mice as compared to wild type mice. It is stated that tetraspanin transmembrane 4 L six family member 5 is particularly involved in hepatic fibrosis development, a disease known in the art for causing ductular reactions.
Regarding claim 4, Ryu et al. teaches the method according to claim 1, wherein in a case where laminin γ2 single chain or a nucleic acid encoding the same is detected, the specimen is likely to contain hepatocytes with bile ductular proliferation or hepatocytes having a liver disease causing bile ductular proliferation (see pg. 55/Abstract, pg. 59/Older TM4SF5-transgenic mice show NASH with progressive fibrosis, disclosing laminin γ2 expression in liver fibrosis development, where immunohistochemical studies reveal overexpression of collagen I and laminin γ2 in tetraspanin transmembrane 4 L six family member 5 mice as compared to wild type mice. It is stated that tetraspanin transmembrane 4 L six family member 5, which can be found overexpressed in hepatocytes, is particularly involved in hepatic fibrosis development, a disease known in the art for causing ductular reactions.).
Regarding claim 5, Ryu et al. teaches the method according to claim 1,which further comprises the step of: detecting a bile ductular proliferation-related marker other than laminin γ2 single chain or a nucleic acid encoding the same (see pg. 59/Older TM4SF5-transgenic mice show NASH with progressive fibrosis, disclosing that in addition to laminin γ2, TM4SF5 mice also exhibit higher collagen I, laminin, and pY705STAT3 level, where immunohistochemical studies revealed the overexpression of collagen I and pY705STAT3).
Regarding claim 9, Ryu et al. teaches the method according to claim 1, wherein the specimen is derived from a subject suspected of having hepatocytes with bile ductular proliferation or hepatocytes having a liver disease causing bile ductular proliferation (see pg. 56/Introduction, disclosing investigating the roles of TM4SF5 in nonalcoholic fatty liver disease using transgenic, KO, and diet- or drug-induced mouse models and primary cells, and liver tissue from human patients.).
Regarding claim 14, Ryu et al. teaches wherein hepatocytes with bile ductular proliferation are cells having a liver disease causing bile ductular proliferation (see pg. 55/Abstract, pg. 59/Older TM4SF5-transgenic mice show NASH with progressive fibrosis, pg. 66/Discussion, disclosing laminin γ2 expression in liver fibrosis development, where immunohistochemical studies reveal overexpression of collagen I and laminin γ2 in tetraspanin transmembrane 4 L six family member 5 (TM4SF5, involved in hepatic fibrosis and cancer) mice as compared to wild type mice. Additionally, Immunostaining for laminin γ2 in the cytoplasm of hepatic carcinoma cells has been reported at the invasive front and laminin γ2 has been reported to be a novel serum biomarker for HCC. Thus, laminin γ2 and collagen I α1 may be promising targets for preventing precancerous liver disease and hepatic cirrhosis (advanced stage hepatic fibrosis).).
Regarding claim 15, Ryu et al. teaches wherein hepatocytes with bile ductular proliferation are cells having a liver disease causing bile ductular proliferation (see pg. 55/Abstract, pg. 59/Older TM4SF5-transgenic mice show NASH with progressive fibrosis, disclosing laminin γ2 expression in liver fibrosis development, where immunohistochemical studies reveal overexpression of collagen I and laminin γ2 in tetraspanin transmembrane 4 L six family member 5 mice as compared to wild type mice. It is stated that tetraspanin transmembrane 4 L six family member 5 is particularly involved in hepatic fibrosis development, a disease known in the art for causing ductular reactions.).
Regarding claim 16, Ryu et al. teaches a kit for detecting hepatocytes with bile ductular proliferation, comprising: a reagent for detecting laminin γ2 single chain or a nucleic acid encoding the same (see pg. 57/Immunohistochemistry and tissue staining, disclosing performing immunohistochemistry on mouse liver tissue by using primary antibodies for laminin γ2 (clone: E-6, sc-28 330).).
Regarding claim 17, Greenbaum et al. teaches wherein hepatocytes with bile ductular proliferation are cells having a liver disease causing bile ductular proliferation (see pg. 772, Serum LG2m Elevation predicts the later development of HCC in CHC patients, disclosing that the measurements of LG2m can be further used to predict HCC risk according to liver fibrosis status (which is known to be a liver disease associated with ductular reactions.).
Regarding claim 18, Ryu et al. teaches the kit according to claim 17, wherein the liver disease causing bile ductular proliferation is selected from the group consisting of primary biliary cholangitis, acute hepatitis, fulminant hepatitis, liver failure, primary sclerosing cholangitis, hepatic fibrosis, biliary atresia, and cholestasis (see pg. 55/Abstract, pg. 59/Older TM4SF5-transgenic mice show NASH with progressive fibrosis, disclosing laminin γ2 expression in liver fibrosis development, where immunohistochemical studies reveal overexpression of collagen I and laminin γ2 in tetraspanin transmembrane 4 L six family member 5 mice as compared to wild type mice. It is stated that tetraspanin transmembrane 4 L six family member 5 is particularly involved in hepatic fibrosis development, a disease known in the art for causing ductular reactions.).
Claims 11-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Taro et al. ("Serum Laminin γ2 Monomer as a Diagnostic and Predictive Biomarker for Hepatocellular Carcinoma", as cited in the IDS).
Regarding claim 11, Taro et al. teaches a method of differentiating hepatocytes with bile ductular proliferation from hepatocytes without bile ductular proliferation which comprises the step of: detecting laminin γ2 single chain or a nucleic acid encoding the same in a specimen, wherein in a case where laminin γ2 single chain or a nucleic acid encoding the same is detected, the specimen is determined to contain hepatocytes with bile ductular proliferation, and in a case where laminin γ2 single chain or a nucleic acid encoding the same is not detected, the specimen is determined not to contain hepatocytes with bile ductular proliferation (see pg. 761/Introduction, pg. 763/HCC Prediction Studies, pg. 772/Serum LG2m Elevation predicts the later development of HCC in CHC patients, disclosing hepatitis C in patients leading to liver fibrosis (associated with ductular reactions), cirrhosis, and hepatocellular carcinoma (HCC). chemiluminescent immunoassay (CLIA) was used by for detecting laminin γ2 monomer (LG2m), which is strongly expressed as a monomeric form at the invasive front in tumor cells. In HCC predictive studies where LG2m was measured in patients, HCC incidence at 3 years was 21.3% and 0% in the LG2m-positive and -negative groups, respectively. The measurements of LG2m can be further used to predict HCC risk according to liver fibrosis status (which is known to be a liver disease associated with ductular reactions).).
Regarding claim 12, Taro et al. teaches wherein hepatocytes with bile ductular proliferation are cells having a liver disease causing bile ductular proliferation (see pg. 772, Serum LG2m Elevation predicts the later development of HCC in CHC patients, disclosing that the measurements of LG2m can be further used to predict HCC risk according to liver fibrosis status (which is known to be a liver disease associated with ductular reactions).).
Regarding claim 13, Taro et al. teaches wherein the liver disease causing bile ductular proliferation is selected from the group consisting of primary biliary cholangitis, acute hepatitis, fulminant hepatitis, liver failure, primary sclerosing cholangitis, hepatic fibrosis, biliary atresia, and cholestasis (see pg. 772, Serum LG2m Elevation predicts the later development of HCC in CHC patients, disclosing that the measurements of LG2m can be further used to predict HCC risk according to liver fibrosis status (which is known to be a liver disease associated with ductular reactions).).
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 6, 10 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Ryu et al. as applied to claim 5, 9 and 16 above, and further in view of Greenbaum et al. (US PG-Pub 20100329986 A1).
Regarding claim 6, Ryu et al. fails to teach wherein the bile ductular proliferation-related marker is one or a plurality of makers selected from the group consisting of SOX9, AQP1, CK7, EpCAM, and Dlkl.
However, in the analogous art of adult hepatic progenitor cells and methods of use thereof, Greenbaum et al. teaches facultative stem cells, described in rodent models as "oval cells" or "intermediate hepatobiliary cells", that have the appearance of small hepatocytes with scant cytoplasm and are postulated to arise from a niche close to the terminal bile ducts, called the canal of Hering. Oval cells are frequently found in "ductular reactions" present in both experimental models of liver injury and in patients with chronic liver disease. Their presence is strongly associated with impaired proliferation of mature hepatocytes, indicating that they represent a reserve hepatic progenitor cell population (see Greenbaum et al., [0005]). The hepatic progenitor cells can express the following markers, such as stem cell factor, Foxl1 CK19, CK7, DIWPref-I, ABCG2, c-kit, thy-I, CD34, OV6, NCAM, EpCAM, Trop2, and alpha fetoprotein (see Greenbaum et al., [0008]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify obtaining the expression of biomarkers related to bile ductular proliferation of Ryu et al. by incorporating other biomarkers such as CK7 in hepatic progenitor cells (as taught by Greenbaum et al.), for the benefit of identifying, isolating, and utilizing adult hepatic stem cells in drug discovery and therapeutic methods (see Greenbaum et al. [0003]).
Regarding claim 10, Ryu et al. fails to teach wherein the specimen is derived from blood or urine of the subject.
However, Greenbaum et al. teaches oval cells frequently found in ductular reactions present in both experimental models of liver injury and in patients with chronic liver disease. Their presence is strongly associated with impaired proliferation of mature hepatocytes, indicating that they represent a reserve hepatic progenitor cell population. A sample is obtained of hepatic cells from a subject for identifying adult biopotential progenitor cells. This sample, "patient sample", or "biological sample", can refer to blood and urine (see Greenbaum et al., [0005], [0085], [0124]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify obtaining the expression of biomarkers related to bile ductular proliferation of Ryu et al. by incorporating obtaining the biomarkers derived from blood or urine samples (as taught by Greenbaum et al.), for the benefit of identifying, isolating, and utilizing adult hepatic stem cells in drug discovery and therapeutic methods (see Greenbaum et al. [0003]).
Regarding claim 19, Ryu fails to teach the kit further comprising a reagent for detecting CK19 or a nucleic acid encoding the same.
However, Greenbaum et al. teaches fluorescent markers, such as eGFP (enhanced Green Fluorescent Protein), that can allow for isolation of hepatic progenitor cells. During an analysis of Foxl1 expressing cells in transgenic mice, eGFP expressing cells that co-label with markers of biliary (CK19) and hepatocyte differentiation (HNF-4a) can be detected (see Greenbaum et al., [0117], [0120]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the reagents used for detecting laminin γ2 of Ryu et al. to incorporate using eGFP as a reagent for detection of CK19 (as taught by Greenbaum et al.), for the benefit of identifying, isolating, and utilizing adult hepatic stem cells in drug discovery and therapeutic methods (see Greenbaum et al. [0003]).
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Ryu et al as applied to claim 1 above, and further in view of Taro et al.
Regarding claim 7, Ryu et al. fails to teach the method according to claim 1, wherein the detection of laminin γ2 single chain or a nucleic acid encoding the same is performed over time.
However, in the analogous art of "Serum Laminin γ2 Monomer as a Diagnostic and Predictive Biomarker for Hepatocellular Carcinoma", Taro et al. teaches evaluating the characteristics of hepatocellular carcinoma (HCC) expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. HCC patients undergoing surgery were evaluated for LG2m levels in serum, recorded before and after surgical resection were measured. Additionally, in predictive HCC studies, 70 chronic hepatitis C patients were evaluated from May 2004 to September 2013 to determine subsequent HCC risk according to serum LG2m levels (see Taro et al., pg. 760/Backgrounds and Aims, pg. 763/Exploratory Studies, pg. 763/HCC Prediction Studies).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify obtaining the expression of laminin γ2 of Ryu et al. by incorporating measuring laminin γ2 at different points in time (as taught by Taro et al.), for the benefit of being able to predict and determine the time to develop liver diseases by comparing data points at different points in time
Allowable Subject Matter
Claim 8 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: The closest prior art, Taro et al. teaches evaluating the characteristics of hepatocellular carcinoma (HCC) expressing laminin γ2 monomer (LG2m), a basement membrane component not detected in normal tissues, for HCC diagnosis. HCC patients undergoing surgery were evaluated for LG2m levels in serum, recorded before and after surgical resection were measured. Additionally, in predictive HCC studies, 70 chronic hepatitis C patients were evaluated from May 2004 to September 2013 to determine subsequent HCC risk according to serum LG2m levels (see Taro et al., pg. 760/Backgrounds and Aims, pg. 763/Exploratory Studies, pg. 763/HCC Prediction Studies).
Taro et al. does not disclose or suggest a change in the amount of CK19 over time, or a comparison made between laminin γ2 and CK19.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Tracy C Colena whose telephone number is (571)272-1625. The examiner can normally be reached Mon-Thus 8:00am-5:00pm.
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/TRACY CHING-TIAN COLENA/ Examiner, Art Unit 1797
/JENNIFER WECKER/Primary Examiner, Art Unit 1797
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