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 .
Claim Status
Claim 52 is amended.
Claims 87 and 89 are cancelled.
Claims 52, and 85-86, 88, and 90-103 are currently under examination.
Withdrawn Rejections
Rejections under 35 USC § 112
The rejection of claims 87 and 89 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends is withdrawn in light of claims cancellation.
Rejections under 35 USC § 103
The rejection of claims 52, 86, 90, and 92-97 under 35 U.S.C. 103 as being unpatentable over Wakatsuki et al (US 2014/0094388 A1) is withdrawn in light of claims amendment.
Double patent rejections
The rejection of claims 52, and 83-103 on the ground of nonstatutory double patenting as being unpatentable over claims 1,26,28,30,32-33,36-38,86-95 of copending Application No. 16953002 is withdrawn in light of Application abandonment.
Edited Rejections Necessitated by Claims Amendment
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claims 52, 85-86, 90, and 98-103 are rejected under 35 U.S.C. 103 as being unpatentable over Wakatsuki et al (US 2014/0094388 A1), in view of Slawin et al (US 2016/0151465 A1).
Regarding claims 52, Wakatsuki et al teach an engineered cardiac tissue construct and methods of using these constructs. ( See abstract). The cardiac construct of Wakatsuki et al comprises of two cell populations including cardiomyocytes (i.e. second population/parenchymal), and fibroblasts (i.e. non-parenchymal cells/ first population/stromal cells), as well as extracellular matrix component ([0023]). Wakatsuki et al teach that the cells for making the cardiac construct may be derived from any suitable animal, including but not limited to, human, mouse, rat, pig, cow, dog, guinea pig, etc. (i.e., mammalian cell populations) ([0025]). Wakatsuki et al state that “the fibroblasts (i.e. the non-parenchymal cell population) can overwhelm the cardiomyocytes by replication such that the resulting tissue does not have the functional properties of cardiac tissue. Thus, the growth of the fibroblasts may need to be limited” ([0032]). According to Wakatsuki et al, the growth ability of the fibroblast cells can be limited by several methods or any means known to those of skill in the art ([0023], [0027]). Among the methods that Wakatsuki et al suggest to limit the growth of the fibroblast cells is by genetically engineering the fibroblast cells to express a suicide gene that can be activated by a small molecule to induce cell killing or inhinting their growth, this reads on step (a) ([0029]). For example, Wakatsuki et al state that “ the fibroblasts may be transfected with the thymidine kinase gene from Herpes Simplex Virus such that the fibroblast cells become sensitive to an antiviral such as ganciclovir” ([0029]). Wakatsuki et al also state that “The cardiac tissues may be formed on a scaffold support disposed within a well”, this reads on step (b) ([0003]).
Taken together, Wakatsuki et al teach a method of producing engineered heart construct comprising of non-parenchymal cell population (i.e. fibroblast) and a second population (i.e. cardiomyocytes). Wakatsuki et al further suggest that the non-parenchymal cells can be eliminated from the tissue construct by genetically engineering the non-parenchymal cells to express a suicide gene. Wakatsuki et al do not specifically exemplify the method of elimination (i.e. step (c)). However, claim 1 would have been obvious to one of ordinary skill in the art at the time the invention was filed, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Because Wakatsuki et al teach a method for making tissue construct comprising of two cell populations, and clearly suggest that the non-parenchymal cell population in the tissue construct can be eliminated by genetically engineering the cells to express a suicidal gene such as thymidine kinase (HSV-TK), wherein the cells are eliminated by contacting the tissue construct with an antiviral (e.g. ganciclovir). Therefore, an ordinary skill in the art would have a reasonable expectation of success, when making a tissue construct, to genetically engineer the non-parenchymal cells to express a suicide gene because doing so which would provide the system with a temporal control, such as controlling the growth of the non-parenchymal cell population in the tissue construct.
It is noted that Wakatsuki et al suggest the use of thymidine kinase as a suicidal gene to control the survival of the non-parenchymal cell population within the construct, wherein the thymidine kinase induces cells death by forming a toxic drug within the cells and does not induce apoptosis and thus Wakatsuki’s et al system is unsuitable for implantation because it may produce bystander killing of neighboring cells. To fill the gap, Slawin et al is cited to supplement Wakatsuki by teaching an inducible caspase systems for controlled induction of apoptosis. Specifically, Slawin et al teach a method that involves engineering therapeutic cells, such as T cells, to express a caspase or a modified version whose activation can be externally triggered, allowing for the tuned elimination of only caspase-expressing cells. Slawin et al utilize an inducible caspase-9 system, in which caspase 9 may have an inducible dimerization domain. (See abstract, [0008],[0010], and [0012]). Slawin et al also demonstrate in vivo contacting the cells with the small molecule to induce the killing of the cells expressing the inducible caspase 9 ( [0353]). Slawin et al additionally teach that thymidine kinase, as taught by Wakatsuki, can result in adverse immune responses ([0320]). Furthermore, Applicants own reference regarding bystander killing demonstrates drawbacks of HSV-TK systems. Thus an ordinary skill in the art would have recognized that alternative inducible cell-elimination systems were available and would have been motivated to employ such alternatives to achieve controlled elimination of cells while avoiding known drawbacks of HSV thymidine kinase systems. An ordinary skill in the art who had viewed Wakatsuki could have come across Slawin and immediately noticed the benefit of incorporating caspas-9 system of Slawin into the engineering construct of Wakatsuki, instead of the thymidine kinase system, in order to provide a controllable cell-elimination mechanism while obtaining the recognized advantages of the apoptosis-based systems. Thus an ordinary skill in the art would have reasonably expected that the incorporation of apoptosis-inducing system of Slawin into the tissue construct of Wakatsuki would yield a construct suitable for implantation. Accordingly, the combined teachings of Wakatsuki and Slawin render obvious the claimed engineered tissue construct suitable for implantation.
Regarding claim 86, Wakatsuki et al further teach that the tissue construct may further comprises co-culturing the cells with a third cell population comprising endothelial cells. (See claim 12).
Regarding claims 85, 98-103, the teaching of Wakatsuki et al and Slawin et al are set forth above. The combined teachings of Wakatsuki et al and Slawin et al render obvious claim 52. Therefore, claims 85, and 98-103 would have been obvious to one of ordinary skill in the art at the time the invention was filed, as there was some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. Because Wakatsuki et al teach a method for making tissue construct comprising of two cell populations, and clearly suggest that the non-parenchymal cell population in the tissue construct can be eliminated by genetically engineering the cells to express a suicidal gene such as thymidine kinase, wherein the cells are eliminated by contacting the tissue construct with an antiviral (e.g. ganciclovir). Slawin et al teach a method for engineering therapeutic cells expressing inducible caspase-9, allowing for the tuned elimination of only a subset of caspase-expressing cells. Slawin et al additionally teach that thymidine kinase, as taught by Wakatsuki, can result in adverse immune responses ([0320]). Therefore, an ordinary skill in the art would be motivated would to use a suicide gene that does not have adverse immunological effects. There would be a reasonable expectation of success in using the inducible caspase 9 of Slawin, instead of the thymidine kinase as taught by Wakatsuki, because Slawin et al demonstrate that caspase-9 can be used in cells to induce apoptosis. One would expect similar results since both references use suicide genes to induce cell apoptosis.
Claims 86,88, and 90-97 are rejected under 35 U.S.C. 103 as being unpatentable over Wakatsuki et al and Slawin et al as applied to claims 52, 85-86, 90, and 98-103 above, and further in view of Chen et al (WO 2017/062757 A1).
Regarding claims 86,88, and 90-97, the teaching of Wakatsuki et al and Slawin et al are set forth above. The combined teachings of Wakatsuki et al and Slawin et al render obvious a tissue construct comprising an engineered non-parenchymal cells that express a suicide gene (i.e. caspase 9), allowing for the tuned elimination of only a subset of caspase-expressing cells . However, neither Wakatsuki et al nor Slawin et al teach a tissue construct wherein the parenchymal cells are hepatocyte or hepatocytes precursor.
Chen et al teach a tissue construct comprising of: a first cell population of primary human hepatocytes (i.e. parenchymal cell) ; a second cell population of human fibroblasts (i.e. first non-parenchymal cell) ; a third cell population of primary human endothelial cells (i.e. second non-parenchymal cell) ; and a biocompatible hydrogel scaffold ( See claim 1). Chen et al also teach that the tissue construct is suitable for implantation into a host (claim 1). Chen et al further teach that the third cell population (i.e. endothelial cells) is seeded into a pre-templated vessels in the substrate to promote vascularization of the engineered tissue construct. (See claims 18-19, and section “ Vascular Cell and Endothelial Cell Cords” on page 25-26). Chen et al do not teach a tissue construct wherein one of the non-parenchymal cell population express a suicide gene. However, instant claims are combining prior art elements according to known methods to yield predictable results, namely the predictable result being a tissue construct comprising of parenchymal and non-parenchymal cell populations, and wherein the non-parenchymal cell population is engineered to express suicide gene. Because Wakatsuki et al in view of Slawin et al render obvious making tissue construct comprising of parenchymal cells and non-parenchymal cell populations, wherein the parenchymal cell population comprising of cardiomyocytes, but fails to teach a construct comprising of hepatocytes. Chen et al supplement Wakatsuki and Slawin by teaching a tissue construct that is suitable for transplantation into a host, wherein the construct comprises of primary human hepatocytes; human fibroblasts ; and a third cell population of primary human endothelial cells. Therefore, an ordinary skill in the art who had reviewed Wakatsuki et al and Slawin et al could have come across Chen et al and immediately noticed the strong possibility that making a tissue construct comprising of hepatocytes as the parenchymal cell type, instead of cardiomyocytes of Wakatsuki et al, would have the predictable result of generating a tissue construct suitable for transplantation into a host.
Response to Arguments
Applicant's arguments filed 06/02/2026 have been fully considered but they are not persuasive.
Applicants argue that Wakatsuki et al. describe engineered heart tissues that are "an in vitro system for modeling and understanding cardiac function" which comprise cardiomyocytes and fibroblast. Wakatsuki et al. do not teach or suggest that the engineered heart tissues are for use in vivo or suitable for implantation. Specifically, Applicants argue that Wakatsuki utilizes a thymidine kinase-based suicide system that induces cell death rather than apoptosis and that according to Mensil et al, the system may cause bystander killing of adjacent cells. Applicants therefore conclude that Wakatsuki is unsuitable for in vivo transplantation.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because the amended rejection does not rely upon Wakatsuki for teaching the claimed apoptosis-inducing polypeptide. As set forth in the rejection above, Slawin is relied upon for teaching apoptosis-inducing caspase polypeptide. Wakatsuki is relied upon for its disclosure of an engineered tissue construct comprising a controllable cell-elimination mechanism within such construct. To the extent Applicants rely upon Mensil et al to identify drawbacks associated with thymidine kinase-mediated cell killing, such evidence does not negate the teachings of Wakatsuki. Rather, the recognition of such disadvantages would have provided additional motivation to employ alternative inducible systems such as the apoptosis-inducing caspase 9 taught by Slawin. Accordingly, Applicants arguments regarding bystander effects do not overcome the prima facie case of obviousness.
Applicants further argue that Slawin et al teach elimination of transplanted parenchymal cells and therefore does not suggest elimination of non-parenchymal cells within a tissue construct.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. Because the rejection does not rely upon Slawin et al for teaching that non-parenchymal cells should be eliminated. Rather, Wakatsuki et al expressly teaches engineered tissue constructs comprising of both parenchymal and non-parenchymal cell population and further teaches the desirability of selectively eliminating the non-parenchymal cell population. Slawin et al is relied upon for teaching apoptosis-inducing polypeptides as a controllable safety mechanism for eliminating genetically modified cells. Slawin et al demonstrate that inducible-caspase-based construct were known in the art as an alternative means of selectively eliminating genetically modified cells. Also, Slawin et al does not teach that the apoptosis-inducing system is limited to parenchymal cells, nor does its operation depend on a particular cell type. Rather, the apoptosis-inducing system of Slawin et al functions upon activation in cells engineered to express the construct. Because Wakatsuki et al already teaches the objectives of selectively eliminating the non-parenchymal, a person of ordinary skill in the art would have been motivated to utilize the apoptosis-inducing polypeptide of Slawin et al as an alternative to the HSV-TK system of Wakatsuki. In other words, the rejection relies upon the predictable application of known apoptosis-inducing system to a known target cell population within the engineered tissue construct of Wakatsuki. Accordingly, the combined teachings of Wakatsuki and Slawin teach the claimed tissue construct comprising of parenchymal and non-parenchymal cell populations, wherein the non-parenchymal cell population comprises a genetic construct encoding an apoptosis-inducing polypeptide.
Applicants also argue that the construct as taught by W akatsuki et al. would induce cell death in cells of the engineered tissue construct that do not express the cell death-inducing polypeptide, and possibly even cause death of adjacent cells from the host, and Chen et al. is silent regarding selective elimination of any cells. Thus, Applicants conclude that a person of ordinary skill in the art would not have any motivation to combine Wakatsuki et al. and Chen et al. to achieve the claimed invention, nor a reasonable expectation of success in doing so.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because the amended rejection does not rely upon Wakatsuki for teaching the claimed apoptosis-inducing polypeptide. As set forth in the rejection above, Slawin is relied upon for teaching apoptosis-inducing caspase polypeptide. Therefore, an ordinary skill in the art who had reviewed Wakatsuki et al and Slawin et al could have come across Chen et al and immediately noticed the strong possibility that making a tissue construct comprising of hepatocytes as the parenchymal cell type, instead of cardiomyocytes of Wakatsuki et al, would have the predictable result of generating a tissue construct suitable for transplantation into a host, wherein the tissue construct comprises of an engineered non-parenchymal cells that express a suicide gene (i.e. caspase 9), allowing for the tuned elimination of only a subset of caspase-expressing cells.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
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