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 .
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed January 12, 2026.
Claims 22-23, 25-37 and 39 are pending in the application, no claims are amended, no new claims have been added and claim 24 has been canceled as set forth in the claim set filed 01/12/2026. Claims 26-27, 29, 32, and 34-35 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/21/2024.
Claims 22-23, 25, 28, 30, 31, 33, 36-37 and 39 are examined on the merits.
Priority
The present application is a CON of Application 16/542,490 filed August 16, 2019 (Now ABN) which was a CON of PCT/US18/18684 filed February 20, 2018. Applicant’s claim for the benefit of a prior-filed parent provisional applications 62/574,119 filed October 18, 2017, and 62/460,267 filed February 17, 2017 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Thus, the earliest possible priority for the instant application is February 17, 2017.
Response to arguments
Withdrawn objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 112
The rejection of claim 24 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second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
Applicant has canceled claim 24, rendering the rejection and all subsequent arguments moot.
Maintained objections/ Rejections in response to Applicants’ arguments or amendments
Claim Rejections - 35 USC § 103
Claims 22-25, 28, 30, 31, 33, 36, 37 and 39 remain rejected under 35 U.S.C. 103 as being unpatentable over Lagasse (US9125891; IDS reference filed 09/19/2023) in view of Cruz-Migoni (2016) Fat-Associated Lymphoid Clusters in Inflammation and Immunity. Front. Immunol. 7:612 ; of record) and DeWard (Curr Opin Organ Transplant. 2014 Apr;19(2):169–174; IDS reference filed 09/19/2023).
Regarding claims 22, 23, and 39, Lagasse teaches a method of transplanting hepatocytes to the lymph node of a subject in order to produce ectopic liver tissue and administering to the subject an agent which induces immunosuppression (i.e. an agent that promotes formation of ectopic tissue) (Claim 1, 13; Col 7, lines 47-67). Lagasse teaches that the lymph nodes utilized are located in a variety of tissue including but not limited to mesenteric lymph nodes, retroperitoneal lymph nodes, abdominal lymph nodes and celiac lymph nodes (Col 1, lines 36-61).
However, Lagasse does not specifically teach that the cells are transplanted to other lymph tissue such as fat associated lymphoid clusters (FALCs) instead of lymph nodes for the purpose of forming ectopic tissue.
Cruz-Migoni teaches the structure and function of FALCs, particularly that FALCs are highly vascularized as shown by their close association to blood vessels (p. 2, last paragraph). Furthermore, FALCs are 100-500 micrometers in mice and size tends to increase with age (Table 2). Unlike lymph nodes, FALCs are not encapsulated and are in direct contact with surrounding adipocytes (p. 2, 1st column).
DeWard teaches common ectopic transplantation sites such as kidney, intraperitoneal space, spleen and lymph nodes (Common ectopic transplantation sites; p. 3-4). DeWard teaches the lymph node is the newest site at the time of the publication which is well vascularized, allowing for transport and rapid expansion of immune cells with a direct access to blood supply which permits angiogenesis and may also support engraftment of both normal and cancer cell in the lymph node (p. 5, paragraphs 2-3). Moreover, promising hepatocyte transplantation in the lymph node has been shown (p. 5, paragraph 3). The limitations of lymph nodes in transplantation is their small size which limits the amount of cells able to be transplanted (p. 5, paragraph 4). Throughout the reference, DeWard emphasizes access to a blood supply in the various ectopic cell transplantation sites lending itself to angiogenesis (p. 3, 2nd paragraph; p. 3, 3rd paragraph; p. 4, 1st paragraph).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to administer the hepatocytes to fat associated lymphoid clusters taught by Cruz-Migoni in place of the lymph nodes of Lagasse with a reasonable expectation of success. An artisan would be motivated to try as DeWard teaches that lymph nodes are well vascularized, allowing for transport and rapid expansion of immune cells with a direct access to blood supply which permits angiogenesis and may also support engraftment of both normal and cancer cell in the lymph node (p. 5, paragraphs 2-3), and Cruz-Migoni teaches fat associated lymphoid clusters are another source of lymphoid tissue which is highly vascularized (p. 2, 1st paragraph). Therefore, an artisan would substitute one highly lymphoid vascularized tissue for another in order to promote angiogenesis and support for ectopic tissue growth.
Regarding claim 25, Lagasse teaches that the implanted subject after being administered hepatocytes to treat patients with end-stage liver disease and demonstrates therapeutic efficacy of restoring liver function (Example 2). It is interpreted that end-stage liver disease is referring to a broader genus which includes disease such as cancer. As Lagasse also teaches that the methods disclosed are useful for treating subsequent liver failure (Col. 6, lines 50-56), it is additionally interpreted that the method treats acute liver failure.
Regarding claim 28, Lagasse teaches that the subject is a human (Claim 13).
Regarding claim 30, Lagasse teaches that the cell source is allogeneic (Col 1, lines 44-46).
Regarding claim 31, Lagasse teaches that the cells are from any source including allogeneic or syngeneic (Col 1, lines 44-46). Therefore autologous cells are included in the scope of “any source.”
Regarding claim 33, 36 and 37, Lagasse teaches that restoration of liver function has been ectopic liver transplantation where hepatocytes are surgically places at a site other than the liver of the patient such as the peritoneum, and that cells are injected into the intraperitoneal cavity (i.e. locally) (Col 1, lines 22-27; Col 8, lines 57-61)
Therefore, the invention as a whole would have been obvious to one of ordinary skill in the art at the time of the effective filing date.
Double Patenting
Claims 22-23, 25, 28, 30, 37 and 39 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 12, 13, and 19 of U.S. Patent No. 9,125,891 (hereinafter Patent ‘891) view of Cruz-Migoni (2016) Fat-Associated Lymphoid Clusters in Inflammation and Immunity. Front. Immunol. 7:612 ; of record) and DeWard (Curr Opin Organ Transplant. 2014 Apr;19(2):169–174; IDS reference filed 09/19/2023). Although the claims at issue are not identical, they are not patentably distinct from each other because:
Regarding claims 22 and 39, Patent ‘891 recites a method of administering hepatocytes to the lymph node of a subject in order to produce ectopic tissue and administering to the subject an agent which induces immunosuppression (i.e. an agent that promotes formation of ectopic tissue) (Claim 1, 13; Col 7, lines 47-67). Patent ‘891 discloses that the lymph nodes utilized are located in a variety of tissue including but not limited to mesenteric lymph nodes, retroperitoneal lymph nodes, abdominal lymph nodes and celiac lymph nodes (Col 1, lines 36-61).
However Patent ‘891 does not specifically teach that the cells are administered to other lymph tissue such as fat associated lymphoid clusters (FALCs) instead of lymph nodes.
Cruz-Migoni teaches the structure and function of FALCs, particularly that FALCs are highly vascularized as shown by their close association to blood vessels (p. 2, last paragraph). Furthermore, FALCs are 100-500 micrometers in mice and size tends to increase with age (Table 2). Unlike lymph nodes, FALCs are not encapsulated and are in direct contact with surrounding adipocytes (p. 2, 1st column).
DeWard teaches common ectopic transplantation sites such as kidney, intraperitoneal space, spleen and lymph nodes (Common ectopic transplantation sites; p. 3-4). DeWard teaches the lymph node is the newest site at the time of the publication which is well vascularized, allowing for transport and rapid expansion of immune cells with a direct access to blood supply which permits angiogenesis and may also support engraftment of both normal and cancer cell in the lymph node (p. 5, paragraphs 2-3). Moreover, promising hepatocyte transplantation in the lymph node has been shown (p. 5, paragraph 3). The limitations of lymph nodes in transplantation is their small size which limits the amount of cells able to be transplanted (p. 5, paragraph 4). Throughout the reference, DeWard emphasizes access to a blood supply in the various ectopic cell transplantation sites lending itself to angiogenesis (p. 3, 2nd paragraph; p. 3, 3rd paragraph; p. 4, 1st paragraph).
Based on such teachings, it would have been obvious to one of ordinary skill in the art at the time of the effective filing date to try to administer the hepatocytes to fat associated lymphoid clusters taught by Cruz-Migoni in place of the lymph nodes of Patent ‘891 with a reasonable expectation of success. An artisan would be motivated to try as DeWard teaches that lymph nodes are well vascularized, allowing for transport and rapid expansion of immune cells with a direct access to blood supply which permits angiogenesis and may also support engraftment of both normal and cancer cell in the lymph node (p. 5, paragraphs 2-3), and Cruz-Migoni teaches fat associated lymphoid clusters are another source of lymphoid tissue which is highly vascularized (p. 2, 1st paragraph). Therefore, an artisan would substitute one highly vascularized tissue for another in order to promote angiogenesis and support for ectopic tissue growth.
Therefore, the instant application is rejected based on double patenting.
In response to Applicant’s arguments against the 103 rejections as well as the Double Patenting rejections under the same rationale,
Applicant’s arguments and amendments filed 01/12/2026 have been considered, however they are not persuasive.
Applicant argues that the rationale provided by DeWard is not sufficient for establishing a reasonable expectation of success, and that other factors provided by DeWard have not been considered. Applicant states that blood supply alone is not sufficient, and that DeWard describes short comings in various transplantation sites which apply to the FALCs of the present invention. Particularly, DeWard states "[t]he transplantation site needs to be relatively accessible, provide sufficient space, offer access to vasculature, and support long-term engraftment" (DeWard at page 6, second paragraph). Applicant further states that lymph nodes are many times greater in size than FALCs based on cited references and it is not clear that FALCs can provide sufficient space. Moreover, Applicant argues that long term engraftment support is not discussed by the references.
Examiner disagrees. DeWard provides a rationale to try FALCs due to the blood supply availability and access to vasculature being known to be an important factor as demonstrated by DeWard and cited by Applicant above. Moreover, DeWard demonstrates that support for cell function is also an important factor and a key point of their paper (p. 10, Key Points) and that locations with access to vasculature provides angiogenesis which sustains cell survival and engraftment of normal tissues (p. 3, last paragraph). DeWard also notes that lymph nodes themselves are limited in size, yet successful engraftment of ectopic tissue has been demonstrated in these small structures (Applicants’ remarks pages 5-6).
Applicant further argues that “DeWard views encapsulation as an advantage for transplantation sites. For example, DeWard states that "lymph nodes are enclosed, so cell engraftment is isolated and can be observed over time" (DeWard at page 5, paragraph 3).” Applicant believes this to mean that the lack of encapsulation of the FALCs would lead to a lack of reasonable expectation of success in growing ectopic tissue.
Examiner disagrees. While DeWard does discuss the advantages of an enclosed space, this does not teach away from the utilization of a space without encapsulation for ectopic tissue. The encapsulation is for monitoring as stated in the above citation by Applicant, not for the efficacy of the overall ectopic tissue formation. Therefore, it does not demonstrate a lack of reasonable expectation of success or teaching away from the utilization of FALCs. Moreover, DeWard describes alternative sites lacking encapsulation (e.g., intraperitoneal space, (Common ectopic transplantation sites; p. 3-4)) and does not categorically exclude non-encapsulated sites. The skilled artisan would not be dissuaded from investigating FALCs based solely on the absence of encapsulation, particularly in light of their vascularization and accessibility.
Moreover, DeWard states that lymph nodes are difficult for transplantation and have many limitations (See p. 5, 4th paragraph) which would lead one of ordinary skill in the art to improve upon a method utilizing lymph nodes.
Applicant states “despite this, the instant application demonstrates, unexpectedly, not only successful engraftment following transplantation of hepatocytes into FALCs, but enhanced survival in an animal model of liver disease (e.g., see Example 3 and FIG. 25).”
Examiner states that even if unexpected results were found, the independent claims are too broad to be in commensurate with the scope of the unexpected results and that additional active steps should be shown within the method.
As Applicant’s arguments against the double patenting rejections are on the basis of the arguments against the 103 rejections, they are additionally not persuasive for the same reasons as above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/ALEXANDRA F CONNORS/ Examiner, Art Unit 1634
/MARIA G LEAVITT/ Supervisory Patent Examiner, Art Unit 1634
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