Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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, 365(c), or 386(c) is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/28/2022 and 04/05/2022 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 19-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims require differentiation of all types of pluripotent cells to differentiate into RPE using the claimed spontaneous differentiation method. However, the specification fails to demonstrate that all pluripotent cells are capable of spontaneously differentiating to RPE as claimed.
At the time of filing of the instant application, iPSCs were not known to a person of ordinary skill in the art. Takahashi et al, in 2006, described that “[d]ifferentiated cells can be reprogrammed to an embryonic-like state by transfer of nuclear contents into oocytes or by fusion with embryonic stem (ES) cells. Little is known about factors that induce this reprogramming. Here, we demonstrate induction of pluripotent stem cells from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Unexpectedly, Nanog was dispensable. These cells, which we designated iPS (induced pluripotent stem) cells, exhibit the morphology and growth properties of ES cells and express ES cell marker genes.” (See Takahashi Abstract; See PTO-892). However, at the time of filing of instant application, one of ordinary skill in the art did not know of the existence of iPSCs. As such it is submitted that instant application did not provide support that all pluripotent stem cells including iPSCs would differentiate in the same manner as hESCs.
Accordingly, the specification does not provide support for the entire scope of the pending claims.
Claims 19-35 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The claims require a method of differentiation of pluripotent cells by providing multilayer of pluripotent cells, culturing the multilayer of cells in a medium lacking certain factors for a sufficient time for the appearance of pigmented cells and isolating, culturing and obtaining RPE cells from the culture.
The claims require isolation of cells upon appearance of pigmented cells. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the method of the invention commensurate in scope with the current claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Applicants' claims are directed to observation of pigmented patches in the multilayer of ESCs. The breadth of the claims includes observation of pigmented patches in ESC multilayer culture by naked eye, which makes the endpoint entirely subjective, undefined and subject to variability. The specification noted that “[a]bout 6 weeks later, dark islands of cells appear within the larger clusters (Fig 1). These dark cells are easily seen with the naked eye and looked like "freckles" in a plate of cells as shown in Fig 1 A.” (See [0058] of instant specification). While the pigments can be observed with naked eye, the claim does not provide guidance regarding the number, density, morphology or intensity of the pigmented cells required to satisfy the claimed end point.
At the time the invention was made it was known that cell differentiation is an unpredictable art. For example, Ogawa (See PTO-892) taught that “[w]hile several models of stem cell differentiation have been proposed, micromanipulation studies of individual progenitors suggest that the commitment of multipotential progenitors to single lineages is a stochastic (random) process.” (See Ogawa Abstract). Therefore, there was a recognized level of unpredictability with regards to differentiation of ESCs.
Due to the lack of teachings in the art regarding RPE differentiation from ESC, and the recognized unpredictability in the area of cell differentiation, a large amount of guidance and teachings would be necessary in order to be enabling for methods of such.
Guidance and teachings provided by Applicants in the instant specification is limited to disclosure to use naked eye to look for freckle-like cells in a plate of cells. The Examiner acknowledges that the Office does not require the presence of working examples to be present in the disclosure of the invention (see MPEP §2164.02). However, in light of the state of the art, discussed above, which recognizes a high level of unpredictability in the field of cell differentiation, and limited teachings with regards to differentiation of ESC to RPE the Office would require appropriate disclosure to support the contention that the claimed method may be successfully employed in the methods of claims 19-35. The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Thus, due to the high level of unpredictability in the art, the current specification would have to provide greater amounts of teachings and guidance directed to methods of carrying out the claimed invention.
Therefore, due to the sum of all the aforementioned factors, one of ordinary skill in the art, at the time the invention was made, would not expect success carrying out the claimed method of spontaneous differentiation. Given that the art fails to recognize and Applicant has failed to demonstrate a reliable way of delineating between RPE cells, the skilled artisan would be faced with the impermissible burden of undue experimentation in order to practice the claimed invention using any species of stem cell. Accordingly, claims 19-35 are deemed properly rejected.
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 19 and 30 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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.
Regarding claim 19 and 30, the phrase "epithelial-like appearance" renders the claim(s) indefinite because the claim(s) include(s) elements not actually disclosed (those encompassed by "epithelial-like appearance"), thereby rendering the scope of the claim(s) unascertainable. See MPEP § 2173.05(d).
Claims 19 and 30 contain the trademark/trade name Plasmanate. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe blood component and, accordingly, the identification/description is indefinite.
Claims 20-29 and 31-35 are rejected for their dependency.
Claim Rejections - 35 USC § 103
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, 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 negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
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 19-20 and 23-24 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kawasaki et al as (Proc Natl Acad Sci U S A. 2002 Feb 5; hereinafter "Kowasaki" See IDS 1/17/2024) evidenced by Marmostein et al (Sci Rep 8, 2018; hereinafter "Marmostein" See IDS 1/17/2024) and Zhang et al (J Assist Reprod Genet. 2012 Aug; hereinafter "Zhang" See PTO-892).
Regarding claim 19: Kawasaki taught culturing monkey ES cell lines with PA6 cells to produce RPE cells. Kawasaki indicated that “[a]fter monkey ES cells were cultured on a PA6 cell layer for 3 weeks, a patch of pigmented cells was mechanically isolated by using a 200-µl tip and plated on a fresh PA6 cell layer (as required by claim 29) in differentiation medium or on collagen I-coated dish in DMEM supplemented with 20 ng/ml bFGF. The pigmented cells grew reasonably fast in both cases and could be replated at least twice.” (See Kawasaki p.1581, col. 2, para 5). The differentiation medium comprised “10% knockout serum replacement/l mM pyruvate/0.1 mM nonessential amino acids/0.1 mM 2-mercaptoethanol” (See Kawasaki p.1581, col. 1, para 1). It is pointed out that the differentiation media of Kawasaki reads on the claimed “media lacking exogenously added basic FGF, LIF and Plasmanate” Further Kawasaki pointed out that “[u]ndifferentiated ES colonies were first washed twice with GMEM medium supplemented with differentiation medium. (See Kawasaki p.1581, col. 1, para 1). ES colonies read on the multilayer of human pluripotent stem cells. (See Evidence in Zhang , “[w]hen human ESCs were allowed to spontaneously differentiate in culture with differentiation medium, the colonies slowly lost their typical undifferentiated morphology and formed multi-layered structures “, p. 740, col. 2, para 1). Kawasaki pointed out that “After culture on PA6 cells for 3 weeks, large patches of pigmented cells were present in 8±4% of the primate ES cell colonies and grew at a constant rate on the feeder cells. The polygonal morphology with a compact cell-cell arrangement (Fig. 5B) was reminiscent of the pigmented epithelium of the eye.” (See Kawasaki p. 1583, col. 2, last para). It is submitted that Kawasaki taught culture of RPE cells by culturing ES cells in a medium lacking bFGF, LIF and Plasmanate. It is noted that the claims do not teach a bestrophin+, cobblestone appearance of the differentiated cells. However, one of ordinary skill would understand as evidenced by Marmostein that these features are inherent of the RPE cells and would expect the claimed cells to exhibit these properties. For example Marmostein indicated that “hexagonal, cobblestone appearance” are typical of RPE cells (See Marmostein p. 4, para 1). Marmostein also indicated that “Best1 is uniquely expressed by RPE cells where it is predominantly localized to the basolateral plasma membrane” (See Marmostein p. 4, para 1).
It would have been obvious to a person of ordinary skill in the art at the time of the invention to employ the culture conditions taught by Kawaski and characterize the resulting pigmented cells using known morphological and molecular markers of the RPE. Kawasaki taught culturing primate ES cells on PA6 feeder cells in differentiation medium, resulting in appearance of large patches of pigmented cells after approximately three weeks of culture. Kawasaki further taught that these cells exhibited a polygonal morphology with compact cell-cell arrangement reminiscent of RPE cells. Zhang provided evidence that ES cells grown in differentiation medium can form multilayered structures, supporting the required multilayer of pluripotent cells in the claim. Additionally Marmostein taught that RPE cells are characterized by cobblestone appearance and are bestrophin+. Because Kawasaki already suggested that the pigmented cells resemble RPE, a skilled artisan would expect such cells to possess the inherent characteristics of RPE. Cobblestone morphology and bestrophin merely reflect inherent properties of RPE and therefor do not meaningfully distinguish the claimed cells from RPE cells as suggested by Kawasaki.
In view of the close biological relationship between human and non-human primates and the known similarities in ESC properties, across primate species, a person of ordinary skill in the art would have had a reasonable expectation that the differentiation behavior observed in primate embryonic stem cell would likewise occur in human embryonic stem cells. (as required by claim 28)
Regarding claim 23: Kowasaki taught dissociation of differentiated ES cells were detached from feeder cells by treatment with collagenase. (See Kowasaki, p. 1582, col. 1, para 2).
Regarding claim 24: As noted above, Kawasaki taught that “After culture on PA6 cells for 3 weeks, large patches of pigmented cells were present in 8±4% of the primate ES cell colonies and grew at a constant rate on the feeder cells.” (See Kawasaki p. 1583, col. 2, last para).A person of ordinary skill in the art would have recognized that adjusting or extending the culture duration to allow further maturation or increased yield of pigmented cells represents a routine optimization well within the skill of the art. Therefore the claimed limitation would have been obvious in view of Kawasaki.
Claims 19-20 and 23-24 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kawasaki et al as (Proc Natl Acad Sci U S A. 2002 Feb 5; hereinafter "Kowasaki" See IDS 1/17/2024) evidenced by Marmostein et al (Sci Rep 8, 2018; hereinafter "Marmostein" See IDS 1/17/2024); and Zhang et al (J Assist Reprod Genet. 2012 Aug; hereinafter "Zhang" See PTO-892) Liggett et al (BMC Cell Biol. 2009 May 4; hereinafter “Liggett;” See PTO-892) and Becerra et al (Exp Eye Res. 2004 Feb; hereinafter “Becerra;” See PTO-892).
Regarding claim 20: As discussed above, Kawasaki reported that formation of RPE cells having polygonal morphology by culturing primate ES cells in a differentiation medium. Retinal pigment cells are inherently known to express characteristic RPE markers such as the claimed bestrophin+, CRALBP+, PEDF+, and express RPE65. For example, Liggett indicated that “RPE-characteristic genes, RPE65 and CRALBP, were used as markers for the identification of RPE cell origin” (See Liggett, p. 2, col. 2, para 5). Further Becerra indicated that “Pigment epithelium-derived factor (PEDF) is an extracellular protein derived from the retinal pigment epithelium (RPE), a tissue formed by polarized cells that release growth and trophic factors in a directional fashion.” (See Becerra Abstract). Accordingly to the extent the pigmented epithelial cells suggested by Kawasaki are retinal pigment epithelial cells, such cells would inherently exhibit the recited expression of PEDF, RPE65, CRALBP and bestrophin, and the recitation of these markers does not meaningfully distinguish the claimed cells.
Claims 21-22 and 30-32 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kawasaki et al as (Proc Natl Acad Sci U S A. 2002 Feb 5; hereinafter "Kowasaki" See IDS 1/17/2024) evidenced by Marmostein et al (Sci Rep 8, 2018; hereinafter "Marmostein" See IDS 1/17/2024) and Zhang et al (J Assist Reprod Genet. 2012 Aug; hereinafter "Zhang" See PTO-892) as applied to claims 19-20 and 23-24; further in view of Gajovic et al (Differentiation. 1997 Dec; hereinafter "Gajovic;" See PTO-892).
Regarding 21 and 22: The teachings of Kowasaki as evidenced by Zhang and Marmostein are set forth above. It is noted that the cited references do not teach expression of Pax6. Gajović taught that “Differentiation of ES cells correlated with increased activity of Pax6, a transcription factor involved in central nervous system development. Pax6 was not expressed in undifferentiated ES cells, nor after differentiation by depletion of leukemia inhibitory factor or by overgrowth.” (See Gajović Abstract). As such one of ordinary skill in the art would expect a mix of Pax6 positive and negative cells in the differentiated RPE produced by the claimed method in view of the teachings of Gajović.
Regarding claim 30 and 31: The teachings of Kowasaki as evidenced by Zhang and Marmostein are set forth above. It is noted that the cited references do not teach differentiation by embryoid bodies. However, Gajovic taught that ESC when cultured in suspension form embryoid bodies (See Gajovic p. 188, col. 1, para 5). Gajovic further taught that embryoid bodies are aggregates of ES cells and undergo spontaneous differentiation by transferring to an adherent cell culture.
It would have been obvious for a person of ordinary skill in the art to generate embryoid bodies using the routine suspension culture as taught by Gajovic and then culture the resulting cells as taught by Kawasaki in the absence of exogenous LIF, bFGF or Plasmanate. Both references taught differentiation of embryonic stem cells and embryoid body formation was well-known method for initiating spontaneous differentiation of such cells. A person of ordinary skill in the art would therefore have found it obvious to employ embryoid body differentiation as an alternative starting format for the ES cell differentiation method taught by Kawasaki.
As indicated above, Kawasaki taught successful differentiation of RPE cells. As such the claim is obvious for the reasons stated.
Regarding claim 32: As discussed above, Kawasaki reported that formation of RPE cells having polygonal morphology by culturing primate ES cells in a differentiation medium. Retinal pigment cells are inherently known to express characteristic RPE markers such as the claimed bestrophin+, CRALBP+, PEDF+, and express RPE65. For example, Liggett indicated that “RPE-characteristic genes, RPE65 and CRALBP, were used as markers for the identification of RPE cell origin” (See Liggett, p. 2, col. 2, para 5). Further Becerra indicated that “Pigment epithelium-derived factor (PEDF) is an extracellular protein derived from the retinal pigment epithelium (RPE), a tissue formed by polarized cells that release growth and trophic factors in a directional fashion.” (See Becerra Abstract). Accordingly to the extent the pigmented epithelial cells suggested by Kawasaki are retinal pigment epithelial cells, such cells would inherently exhibit the recited expression of PEDF, RPE65, CRALBP and bestrophin, and the recitation of these markers does not meaningfully distinguish the claimed cells.
Claims 25 and 26 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kawasaki et al as (Proc Natl Acad Sci U S A. 2002 Feb 5; hereinafter "Kowasaki" See IDS 1/17/2024) evidenced by Marmostein et al (Sci Rep 8, 2018; hereinafter "Marmostein" See IDS 1/17/2024) and Zhang et al (J Assist Reprod Genet. 2012 Aug; hereinafter "Zhang" See PTO-892) as applied to claims 19-20 and 23-24; further in view of Zarbin et al (Trans Am Ophthalmol Soc. 2003; hereinafter "Zarbin;" See PTO-892).
Regarding claims 25 and 26: The teachings of Kowasaki as evidenced by Zhang and Marmostein are set forth above. It is noted that the cited references do not teach passaging of RPE cells or plating on a substrate. However, passaging RPE cells or plating on a substrate was a common routine practice. Cultured adherent cels including epithelial cells and RPE cells. For example Zarbin taught passaging fetal RPE at 1:4 ratio. (See Zarbin p. 505, col. 2, para 1). As such, passaging RPE was well known and routine in the art. It is also pointed out that Zarbin taught that “RPE sheets were dissected out carefully at the end of the incubation using 25-gauge needles, rinsed several times in DMEM, triturated with a 200-μL pipette, and plated on bovine corneal endothelial cell extra cellular matrix (BCE-ECM)-coated dishes.” (See Zarbin p. 505, col. 1, last para).
It would have been obvious for a person of ordinary skill in the art to passage the cells obtained by the methods of Kawasaki or plate them on a coated plate as taught by Zarbin.
Claim 27 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kawasaki et al as (Proc Natl Acad Sci U S A. 2002 Feb 5; hereinafter "Kowasaki" See IDS 1/17/2024) evidenced by Marmostein et al (Sci Rep 8, 2018; hereinafter "Marmostein" See IDS 1/17/2024) and Zhang et al (J Assist Reprod Genet. 2012 Aug; hereinafter "Zhang" See PTO-892) as applied to claims 19-20 and 23-24; further in view of Omran et al (Invest. Ophthalmol. Vis. Sci. 2002; hereinafter "Omran;" See PTO-892).
Regarding claim 27: The teachings of Kowasaki as evidenced by Zhang and Marmostein are set forth above. It is noted that the cited references do not teach suspension culture of RPE. It is noted that suspension cultures of RPE were well-known in prior art. For example, Omran taught that “Freshly isolated RPE cells were transferred in suspension into eppendorf tubes coated with silicone oil, pelleted and stored under various conditions. Viability was assessed at 4 hours and 24 hours in 96 well plates” Omran taught that “[p]igment epithelial cells can be maintained in suspension for up to 24 hours in phosphate buffered saline, without a significant loss of viability. These results indicate that it is possible to maintain pigment epithelial cells without culturing them for at least 24 hours without the loss of viability.” (See Omran Abstract).
Claims 33 and 34 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kawasaki et al as (Proc Natl Acad Sci U S A. 2002 Feb 5; hereinafter "Kowasaki" See IDS 1/17/2024) evidenced by Marmostein et al (Sci Rep 8, 2018; hereinafter "Marmostein" See IDS 1/17/2024) and Zhang et al (J Assist Reprod Genet. 2012 Aug; hereinafter "Zhang" See IDS 1/17/2024) as applied to claims 19-20 and 23-24; further in view of Gajovic et al (Differentiation. 1997 Dec; hereinafter "Gajovic;" See PTO-892) and Zarbin et al (Trans Am Ophthalmol Soc. 2003; hereinafter "Zarbin;" See PTO-892).
Regarding claims 33 and 34: The teachings of Kowasaki in view of Gajovic as evidenced by Zhang and Marmostein are set forth above. It is noted that the cited references do not teach passaging of RPE cells or plating on a substrate. However, passaging RPE cells or plating on a substrate was a common routine practice. Cultured adherent cels including epithelial cells and RPE cells. For example Zarbin taught passaging fetal RPE at 1:4 ratio. (See Zarbin p. 505, col. 2, para 1). As such, passaging RPE was well known and routine in the art. It is also pointed out that Zarbin taught that “RPE sheets were dissected out carefully at the end of the incubation using 25-gauge needles, rinsed several times in DMEM, triturated with a 200-μL pipette, and plated on bovine corneal endothelial cell extra cellular matrix (BCE-ECM)-coated dishes.” (See Zarbin p. 505, col. 1, last para).
It would have been obvious for a person of ordinary skill in the art to passage the cells obtained by the methods of Kawasaki or plate them on a coated plate as taught by Zarbin.
Claim 35 is rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Kawasaki et al as (Proc Natl Acad Sci U S A. 2002 Feb 5; hereinafter "Kowasaki" See IDS 1/17/2024) evidenced by Marmostein et al (Sci Rep 8, 2018; hereinafter "Marmostein" See IDS 1/17/2024) and Zhang et al (J Assist Reprod Genet. 2012 Aug; hereinafter "Zhang" See PTO-892) as applied to claims 19-20 and 23-24; further in view of Gajovic et al (Differentiation. 1997 Dec; hereinafter "Gajovic;" See PTO-892) and Omran et al (Invest. Ophthalmol. Vis. Sci. 2002; hereinafter "Omran;" See PTO-892).
Regarding claim 35: The teachings of Kowasaki in view of Gajovic as evidenced by Zhang and Marmostein are set forth above. It is noted that the cited references do not teach suspension culture of RPE. It is noted that suspension cultures of RPE were well-known in prior art. For example, Omran taught that “Freshly isolated RPE cells were transferred in suspension into eppendorf tubes coated with silicone oil, pelleted and stored under various conditions. Viability was assessed at 4 hours and 24 hours in 96 well plates” Omran taught that “[p]igment epithelial cells can be maintained in suspension for up to 24 hours in phosphate buffered saline, without a significant loss of viability. These results indicate that it is possible to maintain pigment epithelial cells without culturing them for at least 24 hours without the loss of viability.” (See Omran Abstract).
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.
Claims 19-35 are rejected on the ground of nonstatutory double patenting as being unpatentable over indicated claims of U.S. Patent No. indicated below. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims of Instant application
Reference Patent
Claims of Reference application
9040038
19
1
23
2
26
3
9040039
19, 20
1, 2, 7
27
4
26
6
7794704
19, 21
1, 12
24
13-15
21, 20
16
30
21, 31
32
36
8268303
30, 31
1, 3, 4, 28, 30, 31
19, 20
16, 18, 19
23
17
24
20
7795025
19
1, 2, 3, 4, 20
20
8
24
5
30, 31
12, 13, 14, 31, 33-35, 38
7736896
19
1-4, 22-24
20
9, 8
24
5
30
13-16, 29-31
31
21
9040770
19
1,2,4,6
30
5
26
10
27
15
25
16
9080150
19
1-6
9181524
19
1, 3
27
5
26
7
25
2
US9040038B2 as evidenced by Smith et al, and Haghighi et al
Regarding claim 19: Claim 1 of ‘038 patent was directed to production of RPE cells by culturing pluripotent cells to form clusters of cells. The clusters of cells reads on the multilayer of cells as required by instant claim 19. Further claim 1 step (b) of the reference patent requires “culturing the clusters of cells of step (a) under adherent conditions that do not maintain the undifferentiated state of the pluripotent cells for a sufficient time for the appearance of pigmented cells comprising brown pigment dispersed in their cytoplasm.” It is noted that at least bFGF and LIF are important for maintenance of undifferentiated state of stem cells. As such instant step (b) reads on the step (b) of the reference patent. It was well known prior to the filing of the instant application that LIF and bFGF are growth factors necessary for maintenance of undifferentiated state of pluripotent stem cells. (See Smith et al, Nature 1988, p. 688, col. 2, para 1; and Haghighi et al, See Abstract; See PTO-892).
Regarding claims 23 and 26: It is noted that the limitations recited in claims 2 and 3 of ‘038 patent do not render the claimed invention patentably distinct from claims 23 and 26 respectively of the instant application.
US9040039B2 as evidenced by Smith et al, Haghighi et al and Giorgetti et al,
Regarding claim 19: It is noted that Oct-4, alkaline phosphatase, SSEA-3, SSEA-4, TRA-I-60 and TRA-I-81 are all pluripotency or embryonic markers. (Haghighi et al p. 4 col. 2, 1st para; Giorgetti et al p. 2, last para, See PTO-892). Therefore culturing multilayer of cells that do not maintain undifferentiated state of ES which express Oct-4, alkaline phosphatase, SSEA-3, SSEA-4, TRA-I-60 and TRA-I-81 reads on instant step (b) of culturing the multilayer of cells in media lacking exogenously added basic FGF, LIF and Plasmanate. As indicated above, “conditions that do not maintain the undifferentiated state of the pluripotent cells for a sufficient time for the appearance of pigmented cells comprising brown pigment dispersed in their cytoplasm.”
Regarding claim 26-27: It is noted that the limitations recited in claims 4 and 6 of ‘039 patent do not render the claimed invention patentably distinct from claims 26 and 27 respectively of the instant application.
US7794704B2 as evidenced by Smith et al, and Haghighi et al Giorgetti et al
Regarding claim 19: Claim 1 of ‘704 patent was directed to production of RPE cells by culturing pluripotent cells to form clusters of cells. The clusters of cells reads on the multilayer of cells as required by instant claim 19. Further claim 1 step (a)(ii) of the reference patent requires “culturing said multilayer population of hES cells under conditions that do not maintain the undifferentiated state of said hES cells for a sufficient time for the appearance of putative human RPE cells.” It is noted that at least bFGF and LIF are important for maintenance of undifferentiated state of stem cells. As such instant step (b) reads on the step (a)(ii) of the reference patent. It was well known prior to the filing of the instant application that LIF and bFGF are growth factors necessary for maintenance of undifferentiated state of pluripotent stem cells. (See Smith et al, Nature 1988, p. 688, col. 2, para 1; and Haghighi et al, See Abstract; See PTO-892).
Regarding claim 30: Claim 21 of ‘704 patent was directed to production of RPE cells by culturing pluripotent cells to form embryoid bodies and differentiating embryoid bodies. As indicated above, step (a)(iii) of claim 21 of reference application reads on step (b) of instant application for the reasons stated above.
Regarding claims 21, 24, 20, 32: The indicated claims are not patentably distinct from the claims indicated in the reference application in the table above. The limitations of these claims are not patentably distinct from the indicated claims of the reference application.
US8268303B2 as evidenced by Liggett and Becerra
Regarding claim 30: Claim 1 of ‘303 patent was directed to production of RPE cells by culturing pluripotent cells to form embryoid bodies and differentiating embryoid bodies. As indicated above, step (a) of claim 1 of reference application reads on step (b) of instant application for the reasons stated above. Step (c) of isolating and culturing the pigmented cells from the resultant cell cultures, thereby obtaining a culture comprising human RPE cells, wherein said human RPE cells are Pax6−, bestrophin+, CRALBP+, PEDF+, express RPE65 reads on step (c) of the instant application. It is noted that RPE cells inherently express the claimed markers as evidenced by Liggett and Becerra as explained above.
Regarding claim 19: Claim 16 of the reference application reads on the instant claim 19. It is noted that RPE cells inherently express the claimed markers as evidenced by Liggett and Becerra as explained above.
Regarding claims 31, 20, and 23-24: The indicated claims are not patentably distinct from the claims indicated in the reference application in the table above. The limitations of these claims are not patentably distinct from the indicated claims of the reference application.
US7795025B2 as evidenced by Smith et al; Haghighi et al; Liggett, and Becerra
Regarding claim 19: Claim 1 of ‘025 patent was directed to production of RPE cells by culturing pluripotent cells to form clusters of cells. The clusters of cells reads on the multilayer of cells as required by instant claim 19. Further claim 1 step (b) of the reference patent requires “culturing said multilayer population of hES cells under conditions that do not maintain the undifferentiated state of said hES cells for a sufficient time for the appearance of putative human RPE cells.” It is noted that at least bFGF and LIF are important for maintenance of undifferentiated state of stem cells. As such instant step (b) reads on the step (b) of the reference patent. It was well known prior to the filing of the instant application that LIF and bFGF are growth factors necessary for maintenance of undifferentiated state of pluripotent stem cells. (See Smith et al, Nature 1988, p. 688, col. 2, para 1; and Haghighi et al, See Abstract; See PTO-892). It is noted that RPE cells inherently express the claimed markers as evidenced by Liggett and Becerra as explained above.
Regarding claims 20, 24, 30-31: The indicated claims are not patentably distinct from the claims indicated in the reference application in the table above. The limitations of these claims are not patentably distinct from the indicated claims of the reference application.
US7736896B2 as evidenced by Smith et al; Haghighi et al; Liggett, and Gajovic
Claim 1 of ‘896 patent was directed to production of RPE cells by culturing pluripotent cells to form clusters of cells. The clusters of cells reads on the multilayer of cells as required by instant claim 19. Further claim 1 step (b) of the reference patent requires “culturing said multilayer population of hES cells under conditions that do not maintain the undifferentiated state of said hES cells for a sufficient time for the appearance of putative human RPE cells.” It is noted that at least bFGF and LIF are important for maintenance of undifferentiated state of stem cells. As such instant step (b) reads on the step (b) of the reference patent. It was well known prior to the filing of the instant application that LIF and bFGF are growth factors necessary for maintenance of undifferentiated state of pluripotent stem cells. (See Smith et al, Nature 1988, p. 688, col. 2, para 1; and Haghighi et al, See Abstract; See PTO-892). It is noted that RPE cells inherently express the claimed markers as evidenced by Liggett and Gajovic as explained above.
Regarding claims 20, 24, 30-31: The indicated claims are not patentably distinct from the claims indicated in the reference application in the table above. The limitations of these claims are not patentably distinct from the indicated claims of the reference application.
US9040770B2 as evidenced by Smith et al; and Haghighi et al
Regarding claim 19: It is noted that Oct-4, alkaline phosphatase, SSEA-3, SSEA-4, TRA-I-60 and TRA-I-81 are all pluripotency or embryonic markers. (Haghighi et al p. 4 col. 2, 1st para; Giorgetti et al p. 2, last para, See PTO-892). Therefore culturing a multilayer culture of human pluripotent cells that express Oct-4, alkaline phosphatase, SSEA-3, SSEA-4, TRA-I-60, and TRA-I-81 reads on instant step (b) of culturing the multilayer of cells in media lacking exogenously added basic FGF, LIF and Plasmanate.
Regarding claims 30, 25-27: The indicated claims are not patentably distinct from the claims indicated in the reference application in the table above. The limitations of these claims are not patentably distinct from the indicated claims of the reference application.
US9080150B2 and US9181524BS as evidenced by Smith et al; and Haghighi et al
Regarding claim 19: It is noted that Oct-4, alkaline phosphatase, SSEA-3, SSEA-4, TRA-I-60 and TRA-I-81 are all pluripotency or embryonic markers. (Haghighi et al p. 4 col. 2, 1st para; Giorgetti et al p. 2, last para, See PTO-892). Therefore culturing multilayer of cells that do not maintain undifferentiated state of ES which express Oct-4, alkaline phosphatase, SSEA-3, SSEA-4, TRA-I-60 and TRA-I-81 reads on instant step (b) of culturing the multilayer of cells in media lacking exogenously added basic FGF, LIF and Plasmanate. As indicated above, “conditions that do not maintain the undifferentiated state of the pluripotent cells for a sufficient time for the appearance of pigmented cells comprising brown pigment dispersed in their cytoplasm.”
Regarding claims 25-27: The indicated claims are not patentably distinct from the claims indicated in the reference application in the table above. The limitations of these claims are not patentably distinct from the indicated claims of the reference application.
Conclusion
No claim is allowed.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633