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 .
Information Disclosure Statement
The information disclosure statement filed 7/15/2024 has been considered. Citation numbers S* , T*, and U* were not considered, because each does not include a filing date as required. See MPEP § 1.98.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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.
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 24,25,29, 31 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.
In claim 24, the recitation of "density of greater than about 3.6 vessels/mm2 raises an issue of indefiniteness because one does not know the upper limit or density maximum in the implantation site suitable to not inhibit or enhance regeneration as an unlimited microvessel site is encompassed within the scope of greater than 3.6 vessels/mm2 since the clause has no upper limit being an open-ended limitation.
In claim 25, the recitation of "serum ammonia of less than ….50 µmol/L" raises an issue of indefiniteness because one does not know the lower limit or value of the serum ammonia as it could even encompass 0 according to the scope of less than 50 µmol/L since it is an open-ended limitation.
The term “parameter” in claim 25 is a relative term which renders the claim indefinite. The term “parameter” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. One does not know what parameter intended to be measured for comparison to a reference level and thus it is indefinite since such a large number of constituents can be tested for in blood.
The term “improvement” in claims 25,29 is a relative term which renders the claims indefinite. The term “improvement” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. One does not know what degree of measure qualifies for improvement and thus it is ambiguous.
In claim 31, the recitation of "human subject weighs less than 15 kg" raises an issue of indefiniteness because one does not know the lower limit or weight of the patient as it could even encompass 0 according to the scope of less than 15 kg since it is an open-ended limitation.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claim 1 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 24 of copending Application No. 18/704112 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the current application claims are overlapping in scope and merely broader. Narrower claims anticipate the broader claims, see In re Goodman. Claims 1 and 24 combined disclose a method of implanting an engineered tissue construct in a human subject comprising a population of hepatocytes and a population of stromal cells. Since the pending claim of application ‘112 recite the same method and use of same cells, it must perform the same function of treating acute liver failure, especially since pending claim of application ‘112 recited the implanted site is “on a surface of a liver” of copending claim 1. Since the same construct is claimed/disclosed it inherently can perform the same function.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
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.
Claim(s) 1,6-8,13-15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ahlfors (2005/0226856). Ahlfors disclose a method of treating acute liver failure (paragraph 26) in a human subject in need thereof, the method comprising implanting an engineered (paragraph 86) tissue construct (paragraph 22) comprising a population of hepatocytes (paragraph 12) and a population of stromal cells (paragraph 21) wherein the engineered tissue construct provides a microenvironment that promotes the persistence of hepatocyte survival for at least three months in the subject, see paragraph 106 discussing cell recovery using fibroblasts and paragraph 166. Please note since the prior art discloses the claimed construct and cells at the same level of scope, it inherently possesses the same capability of providing a microenvironment (paragraph 85) to promote hepatocyte survival for at least 3 months. Regarding claim 6, it is inherent that Ahlfors provide hepatocytes that are either primary human or expanded human since Ahlfors disclose (abstract) cells are autogenic, thus the cells would be human whether selecting a primary type to seed or reproducing to expand the population. However, in the alternative claim 6 is obvious over Yi et al. (WO 2021/021612) since Ahlfors did not explicitly state the hepatocytes are primary human hepatocytes and/or expanded human hepatocytes. Yi et al. teach producing expanded human hepatocytes for implantation in a patient to treat a liver disease, paragraphs 15-18. It would have been obvious to one of ordinary skill in the art to use expanded human hepatocytes as taught by Yi et al. in the method of liver treatment by Ahlfors such that one has a sufficient regenerated population to effectively treat a patient by implantation. With respect to claim 7, Ahlfors discloses (paragraphs 21,91,94) the construct is provided with fibroblasts. Regarding claim 8, Ahlfors also disclose (paragraphs 184,212) the fibroblasts are selected from the group consisting of normal human dermal fibroblasts and neonatal foreskin fibroblasts. Regarding claims 13,14 Ahlfors discloses (paragraphs 8, 45, 49-60) the engineered tissue construct further includes a biocompatible hydrogel scaffold of which can be fibrin as a known material. With respect to claim 15, Ahfors discloses (paragraphs 26,180) that the implantation site can be an organ such as the liver and placed thereon.
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.
Claim(s) 2,4,11,12,31 are rejected under 35 U.S.C. 103 as being unpatentable over Ahlfors (2005/0226856) in view of Yi et al. (WO 2021/021612). Ahlfors is explained supra. However, Ahlfors did not explicitly disclose the population of hepatocytes includes an amount of hepatocytes that is equivalent to 0.5% to 30% of the total liver mass of the subject. Additionally, Ahlfors did not explicitly disclose the population of hepatocytes includes 3 x 105 to 1.8 x 1011 hepatocytes and/or the population of stromal cells includes up to 1.8 x 1012 stromal cells. Yi et al. teach (paragraphs 14, 18) the treatment of patients for liver disease with hepatocytes can be accomplished with concentrations that encompass a ratio falling within 0.5% to 30% of liver mass and a concentration that encompasses the population delivered to be within 3 x 105 to 1.8 x 1011 hepatocytes. It would have been obvious to one of ordinary skill in the art to select concentrations and ratio of hepatocytes to include in an engineered construct to provide an amount of hepatocytes that is equivalent to 0.5% to 30% of the total liver mass of the subject as taught by Yi et al. in the method of Ahlfors such that a sufficient supply of tissue regenerating cells is provided, paragraph 109. Additionally it would have been obvious to one of ordinary skill in the art to have the population be within a range of 3 x 105 to 1.8 x 1011 hepatocytes as taught by Yi et al. in the method of Ahlfors so that a sufficient amount of cell producing hepatocytes is provided to encourage the regeneration of the liver. It is also noted that Yi et al. teach (paragraph 106) to provide cells in an amount within the range of 1.8 x 1012 cells for a population. Thus, it would have been obvious to one of ordinary skill in the art to have provided a population of stromal cells includes up to 1.8 x 1012 stromal cells per the teaching of Yi et al. in combining these cells with the hepatocytes in the method of treating the liver disease by Ahlfors so that effective regenerative cell volumes are provided. With respect to claim 11, it is noted that Ahlfors discloses (paragraphs 83) that the volume of the construct is taken into consideration in production of the composition of the matrix. However, Ahlfors did not explicitly disclose the engineered tissue construct is from 0.1 mL to 5 L in volume. The examiner takes official notice that cell concentration and construct volume is a result effective variable. Thus, providing the optimal concentration and volume of the tissue construct only involves routine skill in the art, it would have been an obvious expedient to one of ordinary skill to utilize a volume from 0.1 mL to 5L for the engineered construct since it is desirable to produce the optimal regeneration of tissue in the patient. Regarding claim 12, Ahlfors is explained supra. It is noted that Ahlfors disclose (paragraph 81) cell density is critical in promoting cell regeneration. However, Ahlfors did not disclose hepatocytes are at a density of 0.1 M/mL to 150 M/mL. It is also noted that Yi et al. disclose density of the cell population is considered and critical to provide the right amount for the environment. It would have been obvious to one of ordinary skill in the art to select a density as taught by Yi et al. and provide within a density of 0.1 M/mL to 150 M/mL in the method of treating a liver with hepatocytes by Ahlfors such that sufficient tissue regeneration can occur. Regarding claim 31, it is a result effective variable in providing cell populations to the patient body mass of liver. Thus, it is also a matter of design choice to select only patient’s less than 15 kg. Therefore it would have been obvious to one of ordinary skill in the art to select the suitable recipient for an engineered tissue construct and one less than 15 kg in the method of Ahlfors as modified with Yi et al. since both mention optimizing cell population, with respect to patient parameters.
Claim(s) 10 is rejected under 35 U.S.C. 103 as being unpatentable over Ahlfors (2005/0226856) in view of Bhatia et al. (2021/0213173). Ahlfors is explained supra. However, Ahlfors did not explicitly disclose the ratio of hepatocytes to stromal cells is from 1:10 to 4:1. Bhatia et al. teach (see paragraphs 95, 127, claims 6,13,17,22) that a tissue construct with hepatocytes and stromal cells be provided with ratios that fall within a ratio of hepatocytes to stromal cells is from 1:10 to 4:1. It would have been obvious to one of ordinary skill in the art to select an appropriate ratio for hepatocytes to stromal cells in the range from 1:10 to 4:1 as taught by Bhatia et al. in the method of treating a liver disease of a human by Ahlfors such that an effective balance and stimulating environment is provided.
Claim(s) 16 is rejected under 35 U.S.C. 103 as being unpatentable over Ahlfors (2005/0226856) in view of Baer (WO 2014/202199). Ahlfors is explained supra. However, Ahlfors did not explicitly disclose the site specifically being a peritoneum which is the retroperitoneum. Baer teaches (page 30, lines 12-24) that if treating a patient with a tissue engineered scaffold one can implant in the retroperitoneum. It would have been obvious to one of ordinary skill in the art to implant in a site such as the retroperitoneum as taught by Baer in the method of treatment by Ahlfors such that it provides a viable site for cells such as hepatocytes to populate and can treat a liver patient, see Baer.
Claim(s) 16,18 are rejected under 35 U.S.C. 103 as being unpatentable over Ahlfors (2005/0226856) in view of Vacanti et al. (WO 88/03785). Ahlfors is explained supra. However, Ahlfors did not explicitly disclose the site specifically being the peritoneal cavity such as the omentum or the mesentery, wherein the omentum is the greater omentum or the omental bursa or wherein the mesentery is the small intestinal mesentery. Vacanti et al. teach (page 34, lines 13-17) that site of implantation for a cell seeded tissue construct can be the omentum or the mesentery. It would have been obvious to one of ordinary skill in the art to select either the omentum or mesentery as taught by Vacanti et al. in the method of treating a liver patient of Ahlfors such that a site favorable to cell populating can occur. Selecting the appropriate site only involves routine skill in the art and is a result effective variable such that the favorable environment is provided and thus one can select greater omentum or the omental bursa or either the small intestinal mesentery since the surgeon or hepatologist would suggest and select for use the most favorable site for the patient to promote regeneration.
Claim(s) 24 is rejected under 35 U.S.C. 103 as being unpatentable over Ahlfors (2005/0226856) in view of Hoying et al. (CA 3152172). Ahlfors is explained supra. However, Ahlfors did not explicitly disclose the engineered tissue construct is implanted into the subject at an implantation site that has a microvessel density of greater than about 3.6 vessels/mm2. Hoying et al. teach (page 19, lines 8-11) that when treating a patient with a tissue engineered scaffold the microvesel density plays a critical role and about a certain density value optimal regeneration occurs. It would have been obvious to one of ordinary skill in the art to implant in a site that has a microvessel density of greater than about 3.6 vessels/mm2 per the teaching of Hoying et al. for use of optimal microvessel density in the method of treatment by Ahlfors such that it provides a viable site for cells such that the cellular response can occur in suitable conditions. Finding the optimal site only involves routine skill in the art.
Claim(s) 25,27 are rejected under 35 U.S.C. 103 as being unpatentable over Ahlfors (2005/0226856) in view of Chen et al. (WO 2017/062757). Ahlfors is explained supra. However, Ahlfors did not explicitly disclose the subject exhibits a level of change in one or more parameters in a blood test relative to a reference level with one parameter being albumin. Chen et al. teach (Fig. 2A) that after implantation a patient is evaluated for a change in albumin. It would have been obvious to one of ordinary skill in the art to select a reference biomarker to assess a change in activity from results due to implantation of an engineered tissue construct as taught by Chen et al. in the method of treating a liver patient of Ahlfors such that one can determine if suitable cell activity occurred.
Claim(s) 35 is rejected under 35 U.S.C. 103 as being unpatentable over Ahlfors (2005/0226856) in view of Yayon et al. (WO 2006/008748). Ahlfors is explained supra. However, Ahlfors did not explicitly disclose there is a kit with packaging to include instructions for a user to implant an engineered tissue construct. Yayon et al. teach (page 50, lines 29-32, page 51, lines 1,2) that a kit can be provided with a tissue engineered scaffold and have cells seeded to encourage new cellular growth along with a set of instructions for use. It would have been obvious to one of ordinary skill in the art to provide a kit having an engineered tissue construct and instructions for use as taught by Yayon et al. in the method of treatment by Ahlfors such that it provides clear instructions on how the surgeon can implant the engineered tissue construct for good results and treatment to the patient.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRIAN E PELLEGRINO whose telephone number is (571)272-4756. The examiner can normally be reached 8:30am-5:00pm M-F.
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/BRIAN E PELLEGRINO/Primary Examiner, Art Unit 3799
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