Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Action Is Final, Necessitated by Amendment
Applicants' response to the Non-Final Office Action mailed 05 March 2025, has been entered and the Remarks therein, filed 04 September 2025, are fully considered here.
This action is a Final Office Action, based on new grounds under 35 U.S.C. §103(a) over Wang et al. in view of Bhatia et al., and Amit et al., necessitated by Applicants’ amendment received 04 September 2025, specifically, amended claim 19. See MPEP 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
Status of Claims
Claims 19, 21, 23-25 and 28-34 are pending.
Claims 19, 21, 23-25 and 28-34 are rejected.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. §119(e) or under 35 U.S.C. §120, §121, or §365(c) is acknowledged. This application discloses and claims only subject matter disclosed in prior application no. 15/894,842, filed 02/12/2018, which is a CON of 14/791,479, 07/06/2015, which is a CON of 11/917,993, 03/04/2008, which is a 371 of PCT/US2006/023976, 06/20/2006, which claims benefit of 60/693,266, 06/22/2005, and names the inventor or at least one joint inventor named in the prior application. (The specifications filed with applications 16/862,559 and 15/894,842 appear to be the same; i.e., instant application 16/862,559 does not appear to include any subject matter which would constitute new matter (MPEP 201.07).) In addition, the patent (No. 10,676,714) issued from parent application 15/894,842 was issued/published either on the same day or after the filing date of the instant application. Accordingly, this application constitutes a continuation. Applicant has claimed the benefit of the filing date of the prior application, and designates the instant application as a "CON" of 15/894,842.
Applicant has complied with all of the conditions for receiving the benefit of an earlier filing date under 35 U.S.C. §120 or §365(c).
Claims 19, 21, 23-25 and 28-34 have the effective filing date of 22 June 2005.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04 September 2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the Examiner.
Claim Interpretations
(1) Claim 19 recites an intended use in its preamble language.
Claim 19 recites: “A system or kit for maintaining human pluripotent stem (hPS) cells in suspension in a substantially undifferentiated state, comprising undifferentiated hPS cells in suspension in a nutrient medium…and one or more soluble or suspended extracellular matrix components, wherein the system or kit does not comprise microcarriers or microparticles.”
The phrase as an intended use merely states the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention's limitations. Also, the intended use terminology does not limit the structure or method steps of the claimed invention. Therefore, the phrase as an intended use does not limit the scope of the claimed subject matter. (See MPEP 2111.02 (I)(II).) That is, the intended use recited in the preamble does not result in a structural or manipulative difference between the claimed invention and the prior art. Deletion of the preamble phrase does not affect the structure or steps of the claimed invention (MPEP 2111.02 (II)).
In other words, in view of the instantly claimed system which comprises undifferentiated hPS cells in suspension in a nutrient medium that contains about 40ng/mL to about 200ng/mL fibroblast growth factor, and one or more soluble or suspended extracellular matrix (ECM) components, prior art which shows the system components will be considered to be used for maintaining human pluripotent stem (hPS) cells in suspension in a substantially undifferentiated state.
However, at the discretion of the Examiner, any or all of the intended use preamble language will be noted in prior art references which address said language.
(2) Claim 19 recites the indefinite term ‘substantially’.
The specification recites: “Cultures that are substantially undifferentiated contain at least 20% undifferentiated hES cells on an ongoing basis, and may contain at least 40%, 60%, or 80% in order of increasing preference (in terms percentage of cells with the same genotype that are undifferentiated)” (clean copy specification filed 08 May 2023, pg. 5, para. 3).
On the other hand, it is noted that the term ‘substantially’ is recited in the intended use language of the preamble, and may not be addressed during this examination.
(3) Claim 19 recites: "..., comprising undifferentiated hPS cells in suspension in an unconditioned nutrient medium..."
The specification recites: "A 'conditioned medium' is prepared by culturing a first population of cells in a medium, and then harvesting the medium"; "A 'fresh medium' is a medium that has not been purposely conditioned by culturing with a different cell type before being used with the cell type it is ultimately designed to support" (clean copy specification filed 08 May 2023, pg. 6, para. 3 and 4); and "Figure 1 shows colonies of hES cells after six passages on a solid surface in unconditioned medium supplemented with growth factors" (spec., pg. 3, para. 3).
For the purpose of examination, prior art that does not show a step of culturing a population of cells in a medium and then harvesting the medium to produce a culture medium will be considered to show fresh or "unconditioned" medium. It is noted that unconditioned medium, however, may contain other additives or ingredients.
Claim Rejections - 35 U.S.C. § 103
The rejection of Claims 19, 21, 23-25 and 28-34 under pre-AIA 35 U.S.C. §103(a) as being unpatentable over Wang et al. in view of Bhatia et al., and Amit et al., is withdrawn in view of Applicants' amendment received 04 September 2025.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. §102 and §103 (or as subject to pre-AIA 35 U.S.C. §102 and §103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. §103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. §103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. §103(c) and potential pre-AIA 35 U.S.C. §102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. §103(a).
Claims 19, 21, 23-25 and 28-34 are rejected under pre-AIA 35 U.S.C. §103(a) as being unpatentable over Wang et al. (U.S. Patent Application Publication No. 2005/0158852 A1; Pub. Date: Jul. 21, 2005; Filed: Dec. 13, 2004) in view of Bhatia et al. (U.S. Patent Application Publication No. 2005/0282272 A1; Pub. Date: Dec. 22, 2005; Filed: Sep. 24, 2004), and Amit et al. ((2004) Biol. Reprod. 70: 837-845).
[All references cited in the Non-Final Office Action mailed 05 March 2025.]
[This rejection cited in view of Applicant's amendment.]
Wang et al. addresses some of the limitations of claim 19.
Regarding claim 19, pertaining to a system for maintaining hPS cells in a substantially undifferentiated state comprising undifferentiated human pluripotent stem (hPS) cells in suspension in a nutrient medium, wherein the system does not comprise microcarriers, microparticles, or feeder cells,
[See Claim Interpretations section- (1) and (2) above.]
Wang et al. shows a method for culturing undifferentiated human embryonic stem (HES) cells. The method is useful for establishing a clonal HES cell line (pg. 1, para. [0016]). The method comprises the steps of, minimally, obtaining a single undifferentiated HES cell; and mixing the single undifferentiated cell with an extracellular matrix (ECM) to encompass the cell (pg. 1, para. [0017]). The undifferentiated HES cell line identified as HES-3 was used in the described example. The undifferentiated HES cells were dissociated into a single-cell suspension with collagenase. After a centrifugation step to remove collagenase, the pellet containing single cells was resuspended in a(n) HES medium to form a single-cell suspension (pg. 3, para. [0057] thru pg. 4, cont. para. [0057]). Human embryonic stem (HES) cells are pluripotent cell lines that have been derived from the inner cell mass (ICM) of blastocyst stage embryos (pg. 1, para. [0004]). As used herein, the term ‘nutrient medium’ refers to a culturing medium containing nutrients that promote the cells to proliferate (pg. 3, para. [0045]). To maintain HES cells in an undifferentiated state, the HES cells have to be in the conditions that maintain cell proliferation, inhibit ES cell differentiation and preserve pluripotency. The culturing conditions can also be achieved by an extracellular matrix (ECM) instead of feeder cells, which are suitable for culturing small clusters of cells (pg. 2, para. [0032]). In one experiment, 100µl single cell suspension was mixed with 100µl HES extracellular matrix (pg. 4, para. [0068]). The method of culturing single undifferentiated HES cells comprises the steps of obtaining a single undifferentiated HES cell; and mixing the single undifferentiated cell with an extracellular matrix (ECM) to encompass the cell (pg. 2, para. [0034]).
That is, Wang et al. shows undifferentiated hPS cells in suspension in a nutrient (HES) medium, as well as a solution of soluble or suspended extracellular matrix components which are mixed together. Wang et al. does not show microcarriers, microparticles, nor, in one embodiment, feeder cells.
Further regarding claim 19, pertaining to an unconditioned medium,
Wang et al. teaches that methods of preparing nutrient medium for culturing HES cells are well known in the art. A(n) HES medium may typically contain 80% Dulbecco's Modified Eagles Medium (DMEM), 20% defined Fetal Calf Serum, 1 % L-Glutamine, 0.5% penicillin/streptomycin, 1% non-essential amino acids, 1% Insulin-Transferrin- Selenium G supplement and 1 mM β-mercaptoethanol (pg. 3, para. [0047]).
Wang et al. does not show: 1) a nutrient medium that contains 40 ng/mL to 200 ng/mL of fibroblast growth factor (FGF) [Claim 19].
Bhatia et al. addresses some of the limitations of claim 19.
Bhatia et al. shows a system for treating a subject in need of regenerative medicine in which the subject is administered a population of undifferentiated primate pluripotent stem (pPS) cells. Exemplary pPS cells are human embryonic stem (hES) cells or their equivalents (pg. 1, para. [0014]). To obtain a single cell suspension of hES cells, confluent hES cells are removed from culture conditions using trypsin and the cells are triturated into a suspension comprising single cells (pg. 5, para. [0056] [nexus to Wang et al.- undifferentiated hPS cells in suspension]). Scientists at Geron have discovered that pPS cells can be maintained in an undifferentiated state even without feeder cells (pg. 5, para. [0056] [nexus to Wang et al.- a system which does not comprise feeder cells]).
Regarding claim 19, pertaining to a nutrient medium that contains 40 ng/mL to 200 ng/mL of fibroblast growth factor (FGF),
Bhatia et al. shows that pPS cells can be propagated continuously in culture, using culture conditions that promote proliferation while inhibiting differentiation (pg. 5, para. [0055]). Fresh or non-conditioned medium, which has been supplemented with added factors (like a fibroblast growth factor or forskolin) can be used to promote proliferation of the cells in an undifferentiated form. Exemplary is a base medium like X-VIVO™ 10 supplemented with bFGF at 40-80 ng/mL, and optionally containing stem cell factor (15 ng/mL), or Flt3 ligand (75 ng/mL) (pg. 5, para. [0058] [nexus to Wang et al.- suspending pluripotent stem cells in unconditioned medium]).
Amit et al. provides information that would have motivated one of ordinary skill in the art of providing undifferentiated human pluripotent stem cells in suspension in an unconditioned nutrient medium without microcarriers, microparticles or feeder cells, as shown by Wang et al., to include fibroblast growth factor (FGF) in the nutrient medium, as shown by Bhatia et al., by way of addressing the limitations of claim 19.
Regarding claim 19, Amit et al. teaches that human ES (embryonic stem) cells have been shown to maintain all ES cell characteristics when cultured in medium supplemented with bFGF (basic fibroblast growth factor) in a serum-free environment (pg. 837, column 1, para. 1). In the described study, the ability of a serum-free medium supplemented with LIF (leukemia inhibitory factor), TGFβ1 (transforming growth factor-beta1), and bFGF to support prolonged undifferentiated culture of hES cells was examined (pg. 837, column 2, para. 3).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time that the claimed invention was made, to have modified the system for maintaining human pluripotent stem (hPS) cells in suspension in a substantially undifferentiated state, the system comprising undifferentiated hPS cells in suspension in an unconditioned nutrient medium and one or more soluble or suspended extracellular matrix components but without comprising microcarriers, microparticles, or feeder cells, as shown by Wang et al., by: 1) including 40ng/ml to 200ng/ml fibroblast growth factor (FGF) in the nutrient medium [Claim 19], as shown by Bhatia et al., with a reasonable expectation of success, because Bhatia et al. shows a system comprising undifferentiated human embryonic stem cells (hESCs) in suspension in an unconditioned nutrient medium, but which does not comprise microcarriers, microparticles or feeder cells, which is the system, shown by Wang et al. (MPEP 2143 (I)(G)).
One of ordinary skill in the art would have been motivated to have made that modification, because, although Wang et al. does not include FGF in the nutrient medium, Amit et al. teaches and shows that bFGF is well known as a growth factor included in nutrient medium to maintain hESCs in an undifferentiated state. Therefore, it would have been obvious (and one ordinary skill in the art would have been motivated) to have included FGF (specifically, 40ng/ml to 200ng/ml FGF) in the nutrient medium comprising undifferentiated hPS cells and soluble ECM components, as shown by Wang et al., so as to insure that the population of hPS cells would remain substantially undifferentiated (MPEP 2143 (I)(A,G)).
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Wang et al. further addresses the limitations of claims 21, 28, 29, 30 and 32.
Regarding claims 21, 28, 29, 30 and 32, Wang et al. shows that the extracellular matrix can be Matrigel or human extracellular matrix. The extracellular matrix can be prepared from a combination of components selected from a group consisting of, minimally, fibronectin and laminin (pg. 1, para. [0018] thru pg. 2, cont. para. [0018]).
Bhatia et al. further addresses the limitations of claims 24, 25, 31, 33 and 34.
Regarding claims 24, 25, 31, 33 and 34, Bhatia et al. shows that fresh or non-conditioned medium, which has been supplemented with added factors (like a fibroblast growth factor or forskolin) can be used to promote proliferation of the cells in an undifferentiated form. Exemplary is a base medium like X-VIVO™ 10 supplemented with bFGF at 40-80 ng/mL (pg. 5, para. [0058]).
Amit et al. further addresses the limitations of claim 23.
Regarding claim 23, pertaining to TGFβ,
Amit et al. teaches that TGFβ1 is found in Matrigel matrix which supports hES cell growth (pg. 837, column 2, para. 1). In the described study, the ability of a serum-free medium supplemented with LIF, TGFβ1, and bFGF to support prolonged undifferentiated culture of hES cells was examined (pg. 837, column 2, para. 3).
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 claims at issue 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); and 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 Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
(1) Claims 19, 24, 28, 29 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7 and 12 of Patent No. US 7,297,539 B2.
The claimed subject matter of instant Application No. 16/862,559 is:
Claim 19- A system for maintaining human pluripotent stem (hPS) cells in suspension in a substantially undifferentiated state. The system comprises undifferentiated hPS cells in suspension in an unconditioned nutrient medium that contains about 40 ng/mL to about 200 ng/mL of fibroblast growth factor (FGF) and one or more soluble or suspended extracellular matrix components. The system or kit does not comprise microcarriers, microparticles or feeder cells.
The claimed subject matter of Patent No. 7,297,539 is:
Claim 1- A method for proliferating human embryonic stem (hES) cells. The method comprises culturing hES cells in the presence of an extracellular matrix in a medium that comprises a fibroblast growth factor at a concentration of at least 40 ng/mL. The culture is essentially free of feeder cells.
Although the claims are not identical, they are not patentably distinct from each other because, as demonstrated above, in the claim sets from each application, the method for proliferating human embryonic stem cells comprising a medium that contains at least 40ng/ml of fibroblast growth factor and an extracellular matrix component, described in Patent No. 7,297,539, anticipates the system for maintaining human pluripotent stem cells in suspension in a substantially undifferentiated state comprising an unconditioned nutrient medium that contains about 40ng/ml to about 200ng/ml of fibroblast growth factor (FGF) and one or more soluble or suspended extracellular matrix components, but no microcarriers, microparticles or feeder cells, described in instant Application No. 16/862,559.
(2) Claims 19, 23, 24, 28, 29 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 5 and 7-9 of Patent No. 7,410,798 B2.
The claimed subject matter of instant Application No. 16/862,559 is:
Claim 19- A system for maintaining human pluripotent stem (hPS) cells in suspension in a substantially undifferentiated state. The system comprises undifferentiated hPS cells in suspension in an unconditioned nutrient medium that contains about 40 ng/mL to about 200 ng/mL of fibroblast growth factor (FGF) and one or more soluble or suspended extracellular matrix components. The system or kit does not comprise microcarriers microparticles or feeder cells.
The claimed subject matter of Patent No. 7,410,798 is:
Claim 1- A method for culturing a population of human embryonic stem (hES) cells in an undifferentiated state. The method comprises culturing the hES cell population in a culture environment containing: i) an extracellular matrix; ii) a non-conditioned culture medium; and iii) 40 ng/ml of a fibroblast growth factor. The culture environment is essentially free of feeder cells.
Although the claims are not identical, they are not patentably distinct from each other because, as demonstrated above, in the claim sets from each application, the method for proliferating human embryonic stem cells comprising a medium that contains at least 40ng/ml of fibroblast growth factor and an extracellular matrix component, described in Patent No. 7,410,798, anticipates the system for maintaining human pluripotent stem cells in suspension in a substantially undifferentiated state comprising an unconditioned nutrient medium that contains about 40ng/ml to about 200ng/ml of fibroblast growth factor (FGF) and one or more soluble or suspended extracellular matrix components, but not microcarriers, microparticles or feeder cells, described in instant Application No. 16/862,559.
(3) Claims 19 and 23-25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of Patent No. 10,676,714 B2 in view of Mandalam et al. (U.S. Patent Application Publication No. 2003/0017589 A1 (previously cited and on the record).
The claimed subject matter of instant Application No. 16/862,559 is:
Claim 19- A system for maintaining human pluripotent stem (hPS) cells in suspension in a substantially undifferentiated state. The system comprises undifferentiated hPS cells in suspension in an unconditioned nutrient medium that contains about 40 ng/mL to about 200 ng/mL of fibroblast growth factor (FGF) and one or more soluble or suspended extracellular matrix components. The system or kit does not comprise microcarriers, microparticles or feeder cells.
The claimed subject matter of Patent No. 10,676,714 is:
Claim 1- A method for culturing undifferentiated human pluripotent stem (hPS) cells in suspension. The method comprises: a) suspending undifferentiated hPS cells in a cell culture medium comprising basic fibroblast growth factor (bFGF); b) maintaining the hPS cells substantially undifferentiated while culturing in suspension; and c) changing the cell culture medium periodically.
Claim 2- the concentration of bFGF is at least 40 ng/mL.
Claim 3- the concentration of bFGF is about 40 ng/mL.
The claims of Patent No. 10,676,714 do not show: 1) the system comprises one or more (soluble or suspended) extracellular matrix components.
Mandalam et al. teaches that the beneficial effect of the feeder cells can be replaced by providing a suitable surface and a suitable mixture of soluble factors (pg. 3, para. [0034]). pPS (primate pluripotent stem) cells may be supported in feeder-free culture on an extracellular matrix. The described invention contemplates adding extracellular matrix to the fluid phase of a culture at the time of passaging the cells or as part of a regular feeding. The described invention also contemplates extracellular matrix deposited into the culture by cells within the culture. Matrigel® is a soluble preparation from Engelbreth-Holm-Swarm tumor cells (pg. 6, para. [0060]).
Accordingly, it would have been obvious to one of ordinary skill in the art at the time that the claimed invention was made to have modified the claims of Patent No. 10,676,714 with the one or more soluble extracellular matrix components, as shown by Mandalam et al., with a reasonable expectation of success, because Mandalam et al. shows a nutrient medium composition that is used to grow or propagate or maintain primate pluripotent stem cells, which is the composition for culturing hPS cells recited in the claims of Patent No. 10,676,714.
One of ordinary skill in the art would have been motivated to have made that modification because one could have modified the cell culture medium comprising about 40ng/ml bFGF, as shown by Patent No. 10,676,714, with one or more soluble extracellular matrix components, with the reasonably predictable expectation that the undifferentiated human pluripotent stem (hPS) cells would have been successfully cultured (e.g., in suspension).
Although the claims are not identical, they are not patentably distinct from each other because, as demonstrated above in the claim sets from each application, the system for maintaining human pluripotent stem cells in suspension in a substantially undifferentiated state comprising an unconditioned nutrient medium that contains about 40ng/ml to about 200ng/ml of FGF and one or more soluble or suspended extracellular matrix components, but no microparticles, microcarriers or feeder cells, cited in the claims of instant Application No. 16/862,559 is obvious over the cell culture medium used in the method for culturing undifferentiated human pluripotent stem (hPS) cells in suspension, cited in the claims of Patent No. 10,676,714, in view of the cited secondary reference.
Response to Arguments
Applicant’s arguments, pp. 5-9, filed 04 September 2025, with respect to the prior art references cited in the 35 U.S.C. §103 rejection, have been fully considered but they are either not persuasive or are moot because the arguments do not apply to the references as they are applied in the context of the current rejection, or as new grounds necessitated by Applicant’s amendment, in which claim 19 was amended.
1. Applicant remarks (pg. 6, para. 1) that, first, Wang is directed to "improved culturing conditions that allow the growth and survival of single undifferentiated HES cells. The method is useful for establishing a clonal HES cell line." However, in contrast to the teachings of Wang, the claimed system is directed to more than one hPS cell. Accordingly, Applicant submits that the teachings of Wang cannot be modified to be directed to multiple cells as claimed because such a modification would render the methods taught by Wang unsatisfactory for its intended purpose.
However, in response to Applicant, Wang et al. describes the proposed method as one for culturing undifferentiated human embryonic stem cells (plural) (pg. 2, para. [0029]). Although Wang et al. describes the individual steps of the method as they relate to a single undifferentiated cell, it is not clear that the same method would not work using more than one undifferentiated cell. For example, Wang et al. describes several figures (1a-d) as showing the presence of 6-day colonies derived from single undifferentiated HES-3 cells (plural) encompassed with various extracellular matrix (ECM) components. It appears as though the method is described in terms of a single cell in order to emphasize that individual cells are encompassed by ECM. Wang et al. suggests that the method is useful for establishing a clonal HES cell line; i.e., it is not a necessary step of the method.
2. Applicant remarks (pg. 6, para. 3) that, second, the cell culture system taught by Wang is directed to a single cell encompassed by ECM and plated on feeder cells. Specifically, Wang recites that the claimed system "successfully addresses the shortcomings of the presently known configurations by providing methods of culturing single undifferentiated HES cells using an ECM and feeder cells. The claims, as amended herein, are directed to a system for maintaining hPS cells in suspension in a substantially undifferentiated state, wherein the system does not comprise feeder cells.
However, in response to Applicant, although Wang et al. shows in working examples the use of feeder cells, the reference does describe an embodiment in which feeder cells can be replaced by ECM. Wang et al. teaches that to maintain HES cells in an undifferentiated state, the HES cells have to be in the conditions that maintain cell proliferation, inhibit ES cell differentiation, and preserve pluripotency. The culturing conditions can also be achieved by an extracellular matrix (ECM) instead of feeder cells (Wang et al., pg. 2, para. [0032]).
3. Applicant remarks (pg. 7, para. 1) that, third, Wang is cited as teaching a single cell suspension mixed with HES ECM, this mixture was then "transferred to culture dishes with mitomycin-C treated MEF and HEF feeder cells in the presence of the HES medium." That is, the ECM mixture was deposited onto a static culture vessel and is distinct from the HES medium. hPS cells are particularly sensitive to culture conditions, and ECM coated or deposited on a culture vessel is very different from soluble ECM for use in suspension culture. The hPS cells of the claims are in suspension in a nutrient medium, and the claimed one or more soluble ECM components are likewise in the medium. ECM is deposited on a culture vessel for static culture, not suspension culture as claimed.
However, in response to Applicant, Applicant has not provided evidence or explained how hPS cells are (biochemically/biophysically) "different", depending on whether they are ECM coated or deposited on a culture vessel or grown in suspension in the presence of soluble ECM components and does not explain or describe what is meant by hPS 'sensitivity'. This appears to be opinion evidence (MPEP 716.01 (c)(llI)). On the other hand, in one embodiment, Wang et al. shows that, in one experiment, 100µl single cell suspension was mixed with 100µl HES extracellular matrix (pg. 4, para. [0068]). Therefore, it would have been obvious to one of ordinary skill in the art to have tried to have propagated the HES (human embryonic stem) cells in suspension (rather than on a solid substrate with or without feeder cells) in order to maintain their undifferentiated state, barring a showing of criticality for the specific limitation. (For example, the HES cells grown in suspension are "improved" or exhibit identifiable phenotypic characteristics that differ from HES cells grown on a substrate.)
4. Applicant remarks (pg. 7, para. 2 thru pg. 8, para. 1) that Bhatia and Amit do not remedy the deficiencies of Wang, even if combined. Bhatia, like Wang, teaches static culture methods including ECM coated directly on the culture vessel. Moreover, Bhatia fails to teach a suspension culture where cells maintain their pluripotency. Instead, Bhatia teaches that "undifferentiated hES cells differentiate to [embryoid bodies] EBs in suspension culture." Amit was merely cited as teaching "that human ES (embryonic stem) cells have been shown to maintain all ES cell characteristics when cultured in medium supplemented with bFGF (basic fibroblast growth factor) in a serum-free environment.
However, in response to Applicant, in view of the teachings of Amit et al. (i.e., that hES (human embryonic stem) cells have been shown to maintain all ES cell characteristics when cultured in medium supplemented with bFGF) and the teachings of Wang et al. (i.e., that hES can be mixed with ECM components to form a coated cell entity), and Bhatia et al. (i.e. that hES cells can be propagated in suspension, albeit as EBs), one of ordinary skill in the art would have been motivated to have designed the appropriate nutrient medium comprising ECM components, and fibroblast growth factor (FGF), as instantly-claimed, that would support the growth of pluripotent stem cells in suspension as undifferentiated cells.
5. Applicant remarks (pg. 8, para. 3-4), with regard to the double patenting rejections, that the claims of the '539 patent do not teach or suggest a system including undifferentiated hPS cells in suspension in a nutrient medium that contains 40 ng/mL to 200 ng/mL of fibroblast growth factor (FGF) and one or more soluble or suspended extracellular matrix components, wherein the system does not comprise microcarriers or microparticles.
However, in response to Applicant, claim 1 of Patent No. 7,297,539 describes a method for proliferating human embryonic stem (hES) cells, not a system, as noted by Applicant. The method steps comprise culturing hES cells in the presence of extracellular matrix (ECM) in a medium that comprises fibroblast growth factor (at least 40ng/mL concentration) and is essentially free of feeder cells. Therefore, the system described in the instant application anticipates its use in such a method, because the instantly-claimed system comprises a medium that contains 40ng/mL to 200ng/mL of FGF and one or more ECM components.
6. Applicant remarks (pg. 9, para. 1) that the claims of the '798 patent also do not teach or suggest a system including undifferentiated hPS cells in suspension in a nutrient medium that contains 40 ng/mL to 200 ng/mL of fibroblast growth factor (FGF) and one or more soluble or suspended extracellular matrix components, wherein the system does not comprise microcarriers or microparticles.
However, in response to Applicant, claim 1 of Patent No. 7,410,798 describes a method for culturing a population of human embryonic stem (hES) cells in an undifferentiated state, not a system, as noted by Applicant. The method steps comprise culturing hES cell population in a culture environment containing: i) extracellular matrix (ECM); ii) a non-conditioned culture medium; and iii) 40ng/mL of a fibroblast growth tactor, but which is essentially free of feeder cells. Therefore, the system described in the instant application anticipates its use in such a method, because the instantly-claimed system comprises an unconditioned nutrient medium that contains 40ng/mL to 200ng/mL of FGF and one or more ECM components.
7. Applicant remarks (pg. 9, para. 2-4) that the claims of the '589 patent also do not teach or suggest a system including undifferentiated hPS cells in suspension in a nutrient medium that contains 40 ng/mL to 200ng/mL of fibroblast growth factor (FGF) and one or more soluble or suspended extracellular matrix components, wherein the system does not comprise microcarriers or microparticles.)
However, in response to Applicant, this ODP rejection is to Patent No. 10,676,714 and not "the '589 patent", as described above. Claim 1 of Patent No. 10,676,714 describes a method for culturing undifferentiated human pluripotent stem (hPS) cells in suspension. The method comprises: a) suspending undifferentiated hPS cells in a cell culture medium comprising basic fibroblast growth factor (bFGF); b) maintaining the hPS cells substantially undifferentiated while culturing in suspension; and c) changing the cell culture medium periodically. The concentration of bFGF is at least or about 40ng/mL. Therefore, the system described in the instant application anticipates its use in such a method, because the instantly-claimed system comprises undifferentiated hPS cells in suspension, and an unconditioned nutrient medium that contains 40ng/mL to 200ng/mL of FGF and one or more ECM components.
Conclusion
No claims are 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 extension fee 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 date of this final action.
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/SMP/ Examiner, Art Unit 1651
/Adam Weidner/ SPE, Art Unit 1651