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 .
DETAILED ACTION
Claims 1-10 are pending.
Priority
This application, filed on 10/15/2024, claims benefit of 63/590,258 filed 10/13/2023. The effective filing date of the instant application is October 13, 2023.
Drawings
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. 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).
Claim Objections
Claim 7 is objected to because of the following informalities:
Claim 7 recites the acronym “PFIC2” in line 1, which is not preceded by the full name of the disorder at first occurrence in the claim.
Appropriate correction is required.
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, 6-7 and 10 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a mental step without significantly more.
Claim 6 recites the method of claim 1, “wherein when the concentration of TCA is about 25% of the TCA added to the lower chamber or less, it is determined that the allo-antibodies are present; when the concentration of TCA is about 26% to about 75% of the added TCA to the lower chamber, it is indeterminate that the allo-antibodies are present; and when the concentration of TCA is above about 76% or more of the TCA added to the lower chamber, the allo-antibodies are not present.” Thus, the claim is directed to a process (Step 1: Yes)
Claim 10 recites the method of claim 7, “wherein when the concentration of TCA is about 25% of the TCA added to the lower chamber or less, it is determined that the allo-antibodies are present; when the concentration of TCA is about 26% to about 75% of the added TCA to the lower chamber, it is indeterminate that the allo-antibodies are present; and when the concentration of TCA is above about 76% or more of the TCA added to the lower chamber, the allo-antibodies are not present.” Thus, the claim is directed to a process (Step 1: Yes).
The claims set forth a judicial exception of determining that allo-antibodies are present, not present, or indeterminate based on the concentration of TCA, which is a mental step (Step 2A Prong 1: Yes).
This judicial exception is not integrated into a practical application (Step 2A Prong 2: No). There are no additional elements recited in the method (Step 2B: No). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the limitations do not impose any meaningful limitations on practicing the mental step. Hayashi et al. (“Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation” Stem Cell Reports, 2021, Vol. 16, Issue 2, pp.309-323) teaches measuring the amount of bile acid in the upper and lower chambers in a well at 0, 24 and 48 h after loading (p.314-315, Figure 3C). Hayashi teaches that in the two-chamber culture, for BSEPR1090X cells (i.e. modified ABCB11 gene cells), most of the loaded TCA remained in the lower chamber (Figures 3A–3C), which would meet the limitation of the TCA concentration [in the upper chamber] being less than 25% of TCA added to the lower chamber, thus the steps of providing a two-chamber culture vessel; adding taurocholic acid to the lower chamber; adding a serum sample from a subject to the upper chamber; collecting culture medium from each chamber after a period of time; and determining the concentration of TCA in the culture medium of each chamber are well-known, routine and conventional steps in the art.
Kubitz et al. (“Autoimmune BSEP Disease: Disease Recurrence After Liver Transplantation for Progressive Familial Intrahepatic Cholestasis”, Clinical Reviews in Allergy and Immunology, 2015, Vol. 48, pp.273-284) teaches autoimmune BSEP disease (title). Kubitz teaches that progressive familial intrahepatic cholestasis (PFIC) has three subtypes defined by the involved genes: PFIC-1, PFIC-2 and PFIC-3 (abstract). Kubitz further identifies that PFIC-2 is caused by mutations of the ATP binding cassette reporter ABCB11 (bile salt export pump, BSEP) (abstract). Kubitz teaches that in some patients with PFIC-2 disease, recurrence has been observed after liver transplant, and inhibitory anti-BSEP antibodies emerge which most likely cause disease recurrence (abstract). Kubitz teaches that up to 8% of transplanted PFIC-2 patients develop anti-BSEP antibodies, and these patients have elevated serum bile salt (BS) concentrations (p.278, 1st column top paragraph). Kubitz teaches that bile salts are transported through BSEP, and anti-BSEP antibodies inhibit bile salt transport, although the mechanism is not yet known (p.280, 2nd column 2nd paragraph).
Correlating the presence or absence of allo-antibodies based on the concentration of TCA being less than 25%, between 26% and 75%, or above 76% of the TCA added to the lower chamber is a mental step, based on the well-known, routine and conventional steps of measuring TCA concentration in a two-chamber culture vessel as taught by Hiyashi, and the knowledge that the presence of anti-BSEP antibodies inhibits bile salt transport disclosed by Kubitz.
Thus, claims 8 and 10 are rejected under 35 U.S.C. §101.
Claim Rejections - 35 USC § 112
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.
Claims 8 and 10 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 8 recites the limitation "the additional period of time" in line 1. There is insufficient antecedent basis for this limitation in the claim. Claim 8 depends from claim 7, which does not recite “an additional period of time”.
Claim 10 recites the limitation “the allo-antibodies are present” in lines 2, 4 and 5. There is insufficient antecedent basis for this limitation in the claim. Claim 10 depends from claim 7, which does not recite an allo-antibody or allo-antibodies.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2 and 5-10 are rejected under 35 U.S.C. 103 as being unpatentable over Hayashi et al. (“Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Derived Hepatocytes with a Patient-Specific Mutation” Stem Cell Reports, 2021, Vol. 16, Issue 2, pp.309-323) in view of García-Olmo et al. (“Cell-Free Nucleic Acids Circulating in the Plasma of Colorectal Cancer Patients Induce the Oncogenic Transformation of Susceptible Cultured Cells”, Molecular and Cellular Pathobiology, 2010, Vol. 70, Issue 2, pp.560-567) and Kubitz et al. (“Autoimmune BSEP Disease: Disease Recurrence After Liver Transplantation for Progressive Familial Intrahepatic Cholestasis”, Clinical Reviews in Allergy and Immunology, 2015, Vol. 48, pp.273-284).
Regarding claim 1 step a), Hayashi teaches generation of BSEP/ABCB11 mutant human iPSCs [human induced pluripotent stem cell-derived hepatocytes] (p.310, 1st column last paragraph – 2nd column top paragraph). Hayashi teaches an in vitro culture system where iPSCs were differentiated into hepatocyte-like cells on a permeable membrane of a two-chamber (Transwell) system (p.310, 1st column, middle paragraph).
Regarding claim 1 step b), Hayashi teaches adding isotope-labelled D4-TCA into the lower chamber (p.316, Figure 4A; p.318 Figure 5D). Hayashi teaches taurocholic acid (TCA) is the main conjugated bile acid in newborns (p.309, 2nd column top paragraph).
Regarding claim 1 step c), Hayashi does not teach step c) adding a serum sample from the subject into the upper chamber culture medium.
However, Garcia-Olmo teaches the effects on cultured cells of plasma from healthy individuals and from patients with colon cancer (abstract). García-Olmo teaches adding plasma above the insert in Transwell plates (p.562, 1st column paragraph 7). García-Olmo teaches detecting the transfer of human DNA in plasma-treated NIH-3T3 cells (abstract).
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 system of Hayashi to add a sample of serum from a patient as taught by García-Olmo to the upper chamber. Each of Hayashi and García-Olmo teach culturing human cells in a 2-chamber cell culture vessel and detecting compounds in the cell culture medium. One of ordinary skill in the art would have been motivated to add serum samples from a subject into the upper well of the system, because García-Olmo teaches detecting transfer of human DNA in plasma-treated cells through the membrane from the upper chamber to the lower chamber. One of ordinary skill in the art would have found it beneficial to use plasma samples taught by Hayashi to determine the concentration of TCA and improve the clinical value of the detection and quantitation of TCA with respect to the management of patient care.
Regarding claim 1 steps d) and e), Hayashi teaches measuring the amount of bile acid in the upper and lower chambers in a well at 0, 24 and 48 h after loading (p.314-315, Figure 3C).
Hayashi teaches that in the two-chamber culture, for BSEPR1090X cells (i.e. modified ABCB11 gene cells), most of the loaded TCA remained in the lower chamber (i.e. lack of TCA in the culture medium of the upper chamber) (Figures 3A–3C).
Hayashi does not disclose the lack of TCA in the culture medium of the upper chamber indicates that the sample contains allo-antibody against BSEP.
However, Kubitz teaches autoimmune BSEP disease (title). Kubitz teaches that progressive familial intrahepatic cholestasis (PFIC) has three subtypes defined by the involved genes: PFIC-1, PFIC-2 and PFIC-3 (abstract). Kubitz further identifies that PFIC-2 is caused by mutations of the ATP binding cassette reporter ABCB11 (bile salt export pump, BSEP) (abstract). Kubitz teaches that in some patients with PFIC-2 disease, recurrence has been observed after liver transplant, and inhibitory anti-BSEP antibodies emerge which most likely cause disease recurrence (abstract). Kubitz teaches that up to 8% of transplanted PFIC-2 patients develop anti-BSEP antibodies, and these patients have elevated serum bile salt (BS) concentrations (p.278, 1st column top paragraph). Kubitz teaches that bile salts are transported through BSEP, and anti-BSEP antibodies inhibit bile salt transport, although the mechanism is not yet known (p.280, 2nd column 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure the concentration of TCA in the culture medium of the upper chamber and lower chamber as taught by Hiyashi, and conclude that the patient serum sample contains allo-antibodies against BSEP if the upper chamber did not contain TCA, because Kubitz teaches that anti-BSEP antibodies inhibit bile salt transport. One of ordinary skill in the art would reasonably expect that the lack of taurocholic acid (TCA) in the upper chamber would predictably correlate with the presence of anti-BSEP antibodies, because Kubitz teaches that anti-BSEP antibodies prevent the BSEP from transferring TCA, and it was known in the art at the time of invention that the presence of anti-BSEP antibodies resulted in decreased bile salt transport.
Regarding claim 2, Hayashi teaches measuring the amount of bile acid in the upper and lower chambers in a well at 0, 24 and 48 h after loading (p.314-315, Figure 3C).
Regarding claim 5, Hayashi teaches exogenous D4-TCA, 10µM was added to the lower chamber medium (p.320, 1st column 2nd paragraph).
Regarding claim 6, Hayashi teaches most of the loaded TCA remained in the lower chamber for BSEPR1090X cells, whereas the majority of the loaded TCA traversed from the lower to the upper chamber by 48 hours in normal i-Heps (p.313, 2nd column last paragraph; Figures 3A-3C). Based on Figure 3B, the concentration of bile acid in the upper chamber after 48 hours was about 5% for BSEPR1090X cells relative to normal i-Heps cells (100%).
Thus, one of ordinary skill in the art would necessarily be able to determine allo-antibodies are present, based on the concentration of TCA being less than 25% of the TCA added to the lower chamber.
Regarding claim 7 step a), Hayashi teaches the bile salt export pump (BSEP) is responsible for the export of bile acid from hepatocytes, and impaired transcellular transport of bile acids in hepatocytes with mutations in BSEP causes cholestasis (abstract). Hayashi teaches generation of BSEP/ABCB11 mutant human iPSCs [human induced pluripotent stem cell-derived hepatocytes] (p.310, 1st column last paragraph – 2nd column top paragraph). Hayashi teaches an in vitro culture system where iPSCs were differentiated into hepatocyte-like cells on a permeable membrane of a two-chamber system (p.310, 1st column, middle paragraph).
Regarding claim 7 step b), Hayashi teaches adding D4-TCA labelled into the lower chamber (p.316, Figure 4A; p.318 Figure 5D).
Regarding claim 7 step c), Hayashi does not teach step c) adding a serum sample from the subject into the upper chamber culture medium.
However, Garcia-Olmo teaches the effects on cultured cells of plasma from healthy individuals and from patients with colon cancer (abstract). García-Olmo teaches detecting cell-free nucleic acids in the serum and plasma of cancer patients, in particular with respect to the management of such patients (p.560, 2nd column 1st paragraph). García-Olmo teaches adding plasma above the insert in Transwell plates (p.562, 1st column paragraph 7). García-Olmo teaches detecting the transfer of human DNA in plasma-treated NIH-3T3 cells (abstract).
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 system of Hayashi to add a sample of serum from a patient as taught by García-Olmo to the upper chamber. Each of Hayashi and García-Olmo teach culturing human cells in a 2-chamber cell culture vessel and detecting compounds in the cell culture medium. One of ordinary skill in the art would have been motivated to add serum samples from a subject into the upper well of the system, because García-Olmo teaches detecting transfer of human DNA in plasma-treated cells through the membrane from the upper chamber to the lower chamber. One of ordinary skill in the art would have found it beneficial to use plasma samples from subjects with cholestasis taught by Hayashi to determine the concentration of TCA and improve the clinical value of the detection and quantitation of TCA with respect to the management of patient care.
Regarding claim 7 steps d) and e), Hayashi teaches measuring the amount of bile acid in the upper and lower chambers in a well at 0, 24 and 48 h after loading (p.314-315, Figure 3C).
Hayashi does not teach wherein the lack of TCA in the culture medium of the upper chamber indicates that the subject providing the sample will exhibit autoimmunity post gene therapy.
However, Kubitz teaches autoimmune BSEP disease (title). Kubitz teaches that progressive familial intrahepatic cholestasis (PFIC) has three subtypes defined by the involved genes: PFIC-1, PFIC-2 and PFIC-3 (abstract). Kubitz further identifies that PFIC-2 is caused by mutations of the ATP binding cassette reporter ABCB11 (bile salt export pump, BSEP) (abstract). Kubitz teaches that in some patients with PFIC-2 disease, recurrence has been observed after liver transplant, and inhibitory anti-BSEP antibodies emerge which most likely cause disease recurrence (abstract). Kubitz teaches that up to 8% of transplanted PFIC-2 patients develop anti-BSEP antibodies, and these patients have elevated serum bile salt (BS) concentrations (p.278, 1st column top paragraph). Kubitz teaches that bile salts are transported through BSEP, and anti-BSEP antibodies inhibit bile salt transport, although the mechanism is not yet known (p.280, 2nd column 2nd paragraph).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure the concentration of TCA in the culture medium of the upper chamber and lower chamber as taught by Hiyashi, and conclude that the subject providing the sample will exhibit autoimmunity post gene therapy, because Hayashi teaches that most of the loaded TCA remained in the lower chamber, and Kubitz teaches that up to 8% of transplanted PFIC-2 patients develop anti-BSEP antibodies. One of ordinary skill in the art would reasonably expect that the lack of taurocholic acid (TCA) in the upper chamber would predictably correlate with the development of autoimmunity, because Kubitz teaches that anti-BSEP antibodies prevent the BSEP from transferring TCA, and it was known in the art at the time of invention that the anti-BSEP antibodies developed and caused PFIC-2 disease recurrence in PFIC-2 patients post liver transplant.
Regarding claim 8, the limitation “the additional period of time” is being interpreted to require the period of time of claim 7 step d) to be about 24 hours.
Hayashi teaches measuring the amount of bile acid in the upper and lower chambers in a well at 0, 24 and 48 h after loading (p.314-315, Figure 3C).
Regarding claim 9, Hayashi teaches exogenous D4-TCA (10µM) was added to the lower chamber medium (p.320, 1st column 2nd paragraph).
Regarding claim 10, Hayashi teaches most of the loaded TCA remained in the lower chamber for BSEPR1090X cells, whereas the majority of the loaded TCA traversed from the lower to the upper chamber by 48 hours in normal i-Heps (p.313, 2nd column last paragraph; Figures 3A-3C). Based on Figure 3B, the concentration of bile acid in the upper chamber after 48 hours was about 5% for BSEPR1090X cells relative to normal i-Heps cells (100%).
Thus, one of ordinary skill in the art would necessarily be able to determine allo-antibodies are present, based on the concentration of TCA being less than 25% of the TCA added to the lower chamber.
Claims 3-4 are rejected under 35 U.S.C. 103 as being unpatentable over Hayashi et al. (“Modeling Human Bile Acid Transport and Synthesis in Stem Cell-Deed Hepatocytes with a Patient-Specific Mutation” , Stem Cell Reports, 2021, Vol. 16, Issue 2, pp.309-323) in view of García-Olmo et al. (“Cell-Free Nucleic Acids Circulating in the Plasma of Colorectal Cancer Patients Induce the Oncogenic Transformation of Susceptible Cultured Cells”, Molecular and Cellular Pathobiology, 2010, Vol. 70, Issue 2, pp.560-567) as applied to claim 1 above, and further in view of Asai et al. (“Paracrine signals regulate human liver organoid maturation from induced pluripotent stem cells”, Human Development, 2017, Volume 144, Issue 6, pp.1056-1064).
The teachings of Hayashi et al. and García-Olmo et al. are discussed above.
Regarding claims 3 and 4, Hayashi teaches measuring the amount of bile acid in the upper and lower chambers in a well at 0, 24 and 48 h after loading (p.314-315, Figure 3C).
Hayashi and García-Olmo do not teach further comprising culturing the cells for an additional period of time, and collecting culture medium from each of the upper chamber and the lower chamber, and determining the concentration of TCA in the culture medium from each of the upper chamber and the lower chamber (claim 3) or wherein the additional time is about 24 hours (claim 4).
However, Asai teaches culturing HE-iPSC in a two-chamber culture system using a Transwell micropore membrane insert to separate the upper and lower chambers (p.1058, 1st column Fig. 3A). Asai teaches hepatic-specified endoderm iPSCs were plated in the upper chamber (p.1058, 1st column Fig. 3A). Asai further teaches time-course monitoring of albumin production over multiple days of culture, up to 12 days (p.1058, 1st column Fig. 3A).
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 method of Hayashi and García-Olmo to culture the cells to collect culture medium from each of the upper chamber and lower chamber as taught by Hayashi after culturing the cells for an additional period of time as taught by Asai. Each of Hayashi, García-Olmo and Asai teach culturing hepatocytes in a two-chamber culture system and measuring analytes in the culture medium. One of ordinary skill in the art would reasonably expect that culturing the cells for an additional period of time, and selecting a time period of 24 hours would result in the determination of TCA concentration in each of the upper chamber and lower chamber, because Asai teaches sampling the cell culture medium over multiple times points up to 12 days of culture, and it was known in the art at the time of invention that the concentration of TCA in the culture medium could be determined at multiple timepoints.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DEEPA MISHRA whose telephone number is (571) 272-6464. The examiner can normally be reached Monday - Friday 9:30am - 3:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise W. Humphrey can be reached at (571) 272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DEEPA MISHRA/Examiner, Art Unit 1657
Prosecution Insights