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 .
Applicant’s amendment filed on 02/26/2026 has been entered.
Amended claims 1-2, 9-10 and 18-30 are pending in the present application.
Applicant’s election of Group I in the reply filed on 02/26/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant also elected the species of a hepatocyte-derived liver progenitor.
Claims 21-30 were withdrawn from further consideration because they are directed to non-elected inventions.
Accordingly, amended claims 1-2, 9-10 and 18-20 are examined on the merits herein.
Claim Objections
Claim 9 is objected to because of the abbreviation “AFP” should be spelled out in full at the first occurrence of the term.
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 1-2, 9-10 and 18-20 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature, a natural phenomenon, or an abstract idea) without significantly more.
The instant claims are drawn to a liver disease regulatory formulation, comprising a hepatocyte-derived liver progenitor cell; preferably a liver precursor cell or a liver precursor-like cell (claim 2), more preferably a human liver precursor-like cell with an expression level of any one of CD34, CD4 and AFP in the human liver precursor-like cell that is less than 2% (claim 9) or negatively expresses a MHC type II antigen (claim 10); or the same liver disease regulatory formulation, wherein the hepatocyte-derived liver progenitor cell is obtained by culturing a primary hepatocyte in vitro in a hepatocyte expansion and transformation medium that comprises a basal medium, a serum-free additive, a serum-like substance, a growth factor, a TGF-β signal inhibitor, a Wnt signaling pathway agonist and a ROCK inhibitor (claims 18-20). It is noted that claims 18-20 are product-by-process claims. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the rationale explained below.
Analysis for subject matter for nature-based products sets forth 3 inquiries to determine subject eligibility.
The first inquiry is whether the claimed invention is directed to a composition. In the instant case, claims 1-2 and 9-10 are directed to a liver disease regulatory formulation comprising a hepatocyte-derived liver progenitor cell, preferably a liver precursor cell or a liver precursor-like cell, and more preferably a human liver precursor-like cell having an expression level of any one of CD34, CD45 and AFP that is less than 2%, or negatively expresses a MHC type II antigen; while claims 18-20 are drawn to the same liver disease regulatory formulation, wherein the hepatocyte-derived liver progenitor cell is obtained by culturing a primary hepatocyte in vitro in a hepatocyte expansion and transformation medium that comprises a basal medium, a serum-free additive, a serum-like substance, a growth factor, a TGF-β signal inhibitor, a Wnt signaling pathway agonist and a ROCK inhibitor. Thus, the claimed formulation/composition passes the first inquiry. (Step 1, YES).
The second inquiry set forth is whether nature-based products in the composition are exceptions. In the instant case, there is no indication that a hepatocyte-derived liver progenitor cell in the claimed liver disease regulatory formulation of the present application is different from hepatocyte-derived liver progenitors occur in nature as a natural, emergency response to chronic or severe liver injury, and these cells arise from mature hepatocytes that dedifferentiate into a progenitor-like state to regenerate liver tissue when normal hepatocyte proliferation is impaired. Fu et al (Cell Research 29:8-22, 2019) stated “The liver may undergo a systemic injurious responses, upon exposure to a diverse set of metabolic, toxic, and inflammatory insults, resulting in global hepatocellular damage and impaired hepatocyte self-renewal.1 Under circumstances of liver injury, a population of liver progenitor-like cells rapidly emerges and extensively expands…..These findings suggest that both hepatocytes and cholangiocytes might become liver progenitors to rescue hepatocytes during liver injury.6”. Thus, a hepatocyte-derived liver progenitor cell in a liver disease regulatory formulation of the present application encompasses and does not have different characteristics from its natural counterpart in its natural state, and is a “product of nature” exception; and therefore the claims are directed to an exception. Additionally, patent eligibility also requires more than the “hand of man” (e.g., the term isolated or in vitro); and to be eligible the claimed product must be both non-naturally occurring and markedly different from naturally occurring products. Therefore, the claimed formulation/composition passes the second inquiry. (Step 2A, prong one: YES).
Since the claims are directed to a formulation/composition comprising a natural product, the claims do not recite additional steps that integrate the judicial exception into a practical application, and therefore it does not add a meaningful limitation to distinguish the claimed liver disease regulatory formulation comprising a hepatocyte-derived liver progenitor from its naturally occurring counterparts. (Step 2A, prong two: NO).
The third inquiry set forth is whether the claims include additional features that could add significantly more to the exception. In this instance, none of the claims contains any additional features apart from the recited inherent characteristics (e.g., an expression level of any one of CD34, CD45 and AFP in a human liver precursor-like cell is less than 2% and the human liver precursor-like cell negatively expresses a MHC type II antigen in claims 9-10, respectively) that could add significantly more to the exceptions, thus the claims do not qualify as eligible subject matter. Accordingly, the claims are not patent eligible. (Step 2B: NO).
For these reasons the claims are rejected under section 101 as being directed to non-statutory 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.
Claims 1-2, 9-10 and 18-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Fu et al (Cell Research 29:8-22, 2019; Published online: 25 October 2018).
The instant claims encompass a liver disease regulatory formulation, comprising a hepatocyte-derived liver progenitor cell; preferably a liver precursor cell or a liver precursor-like cell (claim 2), more preferably a human liver precursor-like cell with an expression level of any one of CD34, CD4 and AFP in the human liver precursor-like cell is less than 2% (claim 9) or negatively expresses a MHC type II antigen (claim 10); or the same liver disease regulatory formulation, wherein the hepatocyte-derived liver progenitor cell is obtained by culturing a primary hepatocyte in vitro in a hepatocyte expansion and transformation medium that comprises a basal medium, a serum-free additive, a serum-like substance, a growth factor, a TGF-β signal inhibitor, a Wnt signaling pathway agonist and a ROCK inhibitor (claims 18-20). It is noted that claims 18-20 are product-by-process claims.
Fu et al already disclosed a protocol achieving efficient conversion of human primary hepatocytes into liver progenitor-like cells (HepLPCs) by culturing purified isolated human primary hepatocytes in a modified TEM (a transition and expansion medium) comprising DMEM/F12 supplemented with N2 and B27 (serum-free additives), 1mM sodium pyruvate, 10 ug/ml ascorbic acid, 20 ng/ml HGF (a growth factor), 20 ng/ml EGF (a growth factor), 10 uM Y2763 (a ROCK kinase inhibitor), 3 uM CHIR99021 (a GSK-3α/β inhibitor or a Wnt signaling pathway agonist), 1 uM A8301 (a TGF-β signal inhibitor), 1 μM STP and 5 μM LPA (lysophosphatidic acid) (see at least Abstract; sections titled “Conversion of human primary hepatocytes to liver progenitor-like cells” at pages 9-10; “Human primary hepatocyte isolation and purification” and “Cell expansion” at page 19). Fu et al stated “TEM-induced proliferating cells displayed typical features of progenitor cells with a high nucleus/cytoplasm ratio (Fig. 1b). Gene and protein expression levels of multiple hepatic markers decreased while LPC markers increased gradually under the TEM culture conditions, suggesting progressive hepatocyte-to-LPC conversion (Fig. 1c-e)” (left column, first paragraph at page 10); and “These HepLPCs could be expanded significantly during in vitro passage. The expanded cells can readily be converted back into metabolically functional hepatocytes in vitro and upon transplantation in vivo” (Abstract).
Since the expanded human primary hepatocyte-derived liver progenitor-like cells (HepLPCs) of Fu et al are generated in a culture method that is substantially similar to that of the present application and the generated HepLPCs have similar properties (e.g., can be differentiated into metabolically functional hepatocytes in vitro and upon transplantation in vivo); such HepLPCs would inherently have an expression level of any one of CD34, CD45 and AFP to be less than 2% and/or are negative for a MHC type II antigen. Thus, a composition comprising human primary hepatocyte-derived liver progenitor-like cells (HepLPCs) of Fu et al is identical to the claimed formulation comprising a hepatocyte-derived liver progenitor cell of the present application.
Please, also note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
Accordingly, the teachings of Fu et al meet every limitation of the instant claims. Therefore, the reference anticipates the instant claims.
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.
Alternatively, claims 1-2, 9-10 and 18-20 are rejected under 35 U.S.C. 103 as being unpatentable over Fu et al (Cell Research 29:8-22, 2019; Published online: 25 October 2018).
The instant claims encompass a liver disease regulatory formulation, comprising a hepatocyte-derived liver progenitor cell; preferably a liver precursor cell or a liver precursor-like cell (claim 2), more preferably a human liver precursor-like cell with an expression level of any one of CD34, CD4 and AFP in the human liver precursor-like cell is less than 2% (claim 9) or negatively expresses a MHC type II antigen (claim 10); or the same liver disease regulatory formulation, wherein the hepatocyte-derived liver progenitor cell is obtained by culturing a primary hepatocyte in vitro in a hepatocyte expansion and transformation medium that comprises a basal medium, a serum-free additive, a serum-like substance, a growth factor, a TGF-β signal inhibitor, a Wnt signaling pathway agonist and a ROCK inhibitor (claims 18-20). It is noted that claims 18-20 are product-by-process claims.
Fu et al already disclosed a protocol achieving efficient conversion of human primary hepatocytes into liver progenitor-like cells (HepLPCs) by culturing purified isolated human primary hepatocytes in a modified TEM (a transition and expansion medium) comprising DMEM/F12 supplemented with N2 and B27 (serum-free additives), 1mM sodium pyruvate, 10 ug/ml ascorbic acid, 20 ng/ml HGF (a growth factor), 20 ng/ml EGF (a growth factor), 10 uM Y2763 (a ROCK kinase inhibitor), 3 uM CHIR99021 (a GSK-3α/β inhibitor or a Wnt signaling pathway agonist), 1 uM A8301 (a TGF-β signal inhibitor), 1 μM STP and 5 μM LPA (lysophosphatidic acid) (see at least Abstract; sections titled “Conversion of human primary hepatocytes to liver progenitor-like cells” at pages 9-10; “Human primary hepatocyte isolation and purification” and “Cell expansion” at page 19). Fu et al stated “TEM-induced proliferating cells displayed typical features of progenitor cells with a high nucleus/cytoplasm ratio (Fig. 1b). Gene and protein expression levels of multiple hepatic markers decreased while LPC markers increased gradually under the TEM culture conditions, suggesting progressive hepatocyte-to-LPC conversion (Fig. 1c-e)” (left column, first paragraph at page 10); and “These HepLPCs could be expanded significantly during in vitro passage. The expanded cells can readily be converted back into metabolically functional hepatocytes in vitro and upon transplantation in vivo” (Abstract).
Although Fu et al did not explicitly a liver disease regulatory formulation, comprising a hepatocyte-derived liver progenitor cell, including the human liver precursor-like cell having an expression level of any one of CD34, CD45 and AFP of less than 2% (claim 9), or is negative for a MHC type II antigen (claim 10), or is obtained by culturing a primary hepatocyte in vitro in a hepatocyte expansion and transformation medium that comprises the specific components recited in claims 18-20, it would have been obvious for an ordinary skill in the art to recognize that since the expanded human primary hepatocyte-derived liver progenitor-like cells (HepLPCs) of Fu et al are generated in a culture method that is substantially similar to that of the present application and the generated HepLPCs have similar properties (e.g., can be differentiated into metabolically functional hepatocytes in vitro and upon transplantation in vivo); such HepLPCs would necessarily have an expression level of anyone of CD34, CD45 and AFP to be less than 2% or are negative for a MHC type II antigen. Thus, a composition comprising human primary hepatocyte-derived liver progenitor-like cells (HepLPCs) of Fu et al is indistinguishable from the claimed formulation comprising a hepatocyte-derived liver progenitor cell of the present application.
Please, also note that where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. See In re Ludtke. Whether the rejection is based on "inherency" under 35 USC 102, or "prima facie obviousness" under 35 USC 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO's inability to manufacture products or to obtain and compare prior art products. In re Best, Bolton, and Shaw, 195 USPQ 430, 433 (CCPA 1977) citing In re Brown, 59 CCPA 1036, 459 F.2d 531, 173 USPQ 685 (1972).
Therefore, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Kholodenko et al (Cell 2019, 8, 1127; doi:10.3390/cells8101127; 37 pages) reviewed mesenchymal stem cells in the adult human liver that lack expression of CD34, CD45 and HLA-DR (MHC type II antigen) and low expression of α-fetoprotein (see Table 2 at pages 10-11).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Quang Nguyen, Ph.D., at (571) 272-0776.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s SPE, James Douglas (Doug) Schultz, Ph.D., may be reached at (571) 272-0763.
To aid in correlating any papers for this application, all further correspondence regarding this application should be directed to Group Art Unit 1631; Central Fax No. (571) 273-8300.
Any inquiry of a general nature or relating to the status of this application or proceeding should be directed to (571) 272-0547.
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/QUANG NGUYEN/Primary Examiner, Art Unit 1631
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