Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED ACTION
Status of Application/Election/Restrictions
Claims 1-242 are canceled. Claims 243-270 are pending in this application and under examination in this office action.
Specification
The disclosure is objected to because of the following informalities:
i. The Application No. 14/362775 was issued as US Patent No.9752118 and the Application No. 15/666518 was issued as US Patent No. 12049462. Appropriate correction is required.
ii. The recitation “PDGFRb□” recited on p. 33, line 2 of the specification filed 06/13/2204 is objected to because it is unclear what “PDGFRb□” means. Appropriate correction is required.
iii. The attempt to incorporate subject matter into this application by reference to
"human PDGFB polypeptide, such as NP_002599.1" in [00191] of instant specification
and "human DKK2 polypeptide, such as NP_055236.1" in [00194] of specification is ineffective because the specification depends on the description of
GenBank accession numbers to define the polypeptides encompassed by the claims,
but since accession numbers can be updated, the specification fails to define the
claimed sequences and therefore the claims include any number of undefined variants.
For example, Accession No. X87832 has been updated eight times since its initial
submission. It is unclear which sequence, the initial or the updated, should be used in
the claimed method. Thus, the claims are indefinite.
In addition, based on MPEP 608.01(p) Completeness, the recitation of GenBank
accession Nos. to define genes/proteins in the claims is inappropriate because the
genes/proteins as defined by accession no. are essential materials, which are required
by the claimed method. Thus, the incorporation by reference as by recitation of
GenBank accession no. is not effective. The incorporation of essential material in the
specification by reference to an accession number for a PDGFB or DKK2 polypeptide is
improper. Applicant is required to amend the disclosure to include the material
incorporated by reference, if the material is relied upon to overcome any objection,
rejection, or other requirement imposed by the Office. The amendment must be
accompanied by a statement executed by the applicant, or a practitioner representing
the applicant, stating that the material being inserted is the material previously
incorporated by reference and that the amendment contains no new matter. 37 CFR
1.57(f). Also See MPEP 608.01 (p). I. Incorporation by reference & 37CFR 1.57.
Incorporation by reference:
"(c) "Essential material" may be incorporated by reference, but only by way of an incorporation by reference to a U.S. patent or U.S. patent application publication, which patent or patent application publication does not itself incorporate such essential material by reference. "Essential material" is material that is necessary to: (1) Provide a written description of the claimed 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 set forth the best mode contemplated by the inventor of carrying out the invention as required by the first paragraph of 35 U.S.C. 112; (2) Describe the claimed invention in terms that particularly point out and
distinctly claim the invention as required by the second paragraph of 35 U.S.C. 112..."
The incorporation by reference will not be effective until correction is made to
comply with 37 CFR 1.57(c), (d), or (e). If the incorporated material is relied upon to
meet any outstanding objection, rejection, or other requirement imposed by the Office,
the correction must be made within any time period set by the Office for responding to
the objection, rejection, or other requirement for the incorporation to be effective.
Compliance will not be held in abeyance with respect to responding to the objection,
rejection, or other requirement for the incorporation to be effective. In no case may the
correction be made later than the close of prosecution as defined in 37 CFR 1.114(b), or
abandonment of the application, whichever occurs earlier.
Any correction inserting material by amendment that was previously incorporated
by reference must be accompanied by a statement that the material being inserted is
the material incorporated by reference and the amendment contains no new matter. 37
CFR 1.57(g).
Claim Objections
4. Claims 243 and 262-264 are objected to because of the following informalities:
i. The limitations "LRP5/6, Dkk1, Dkk3, Dkk4, LEF/TCF, IWR, ICG-001, PKF115-584, IWP, Ant1.4Br/Ant1.4C1, XAV939, NSC668036, APC, IQ1, WAY-316606, QS11, SB-216763, DCA, PDGFRB, PKC, PDGFAA, PDGFAB" recited in claim 243 and the limitations “Sox10, AP2, HNK1, Pax3, PAX7, ZO-1,KLF-13, AQP1, SLC16A3, CFTR, NBC1, CA2, AE2/SCL4A2, SCL16A1, CA12, CA4, FoxC1, vWF” recited in claims 262-264 are not unique or common abbreviations in the art. Applicants are required to spell out "LRP5/6, Dkk1, Dkk3, Dkk4, LEF/TCF, IWR, ICG-001, PKF115-584, IWP, Ant1.4Br/Ant1.4C1, XAV939, NSC668036, APC, IQ1, WAY-316606, QS11, SB-216763, DCA, PDGFRB, PKC, PDGFAA, PDGFAB" recited in claim 243 and “Sox10, AP2, HNK1, Pax3, PAX7, ZO-1,KLF-13, AQP1, SLC16A3, CFTR, NBC1, CA2, AE2/SCL4A2, SCL16A1, CA12, CA4, FoxC1, vWF” recited in claims 262-264 at the first usage. Appropriate correction is required.
ii. Claim 243 is objected to because the claim recites "comprising (a)
contacting neural crest stem cells...". However, there is no additional step recited after
the step (a). Since the claim recites only one step "contacting...", it is grammatically
awkward to recite (a). Appropriate correction is required.
Claim Rejections - 35 USC § 112
5. 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 243-270 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
Claims 243-270 are indefinite because:
i. Claims 243 and 262-264 are indefinite because the terms "LRP5/6, Dkk1, Dkk3, Dkk4, LEF/TCF, IWR, ICG-001, PKF115-584, IWP, Ant1.4Br/Ant1.4C1, XAV939, NSC668036, APC, IQ1, WAY-316606, QS11, SB-216763, DCA, PDGFRB, PKC, PDGFAA, PDGFAB" recited in claim 243, the terms “Sox10, AP2, HNK1, Pax3, PAX7, ZO-1,KLF-13, AQP1, SLC16A3, CFTR, NBC1, CA2, AE2/SCL4A2, SCL16A1, CA12, CA4, FoxC1, vWF” recited in claims 262-264 without a reference to a precise amino acid sequence identified by a proper SEQ ID NO:, a structure or providing a full name for abbreviated names. Without identification of property or combination of properties which are unique to and, therefore, definitive of the instant recitations, the metes and bounds of the claims remain undetermined. Further, the use of laboratory designations only to identify a particular molecule renders the claims indefinite because different laboratories may use the same laboratory designations to define completely distinct molecules. The rejection can be obviated by amending the claims to specifically and uniquely identify "LRP5/6, Dkk1, Dkk3, Dkk4, LEF/TCF, IWR, ICG-001, PKF115-584, IWP, Ant1.4Br/Ant1.4C1, XAV939, NSC668036, APC, IQ1, WAY-316606, QS11, SB-216763, DCA, PDGFRB, PKC, PDGFAA, PDGFAB" recited in claim 243 and “Sox10, AP2, HNK1, Pax3, PAX7, ZO-1,KLF-13, AQP1, SLC16A3, CFTR, NBC1, CA2, AE2/SCL4A2, SCL16A1, CA12, CA4, FoxC1, vWF” recited in claims 262-264.
ii. Claim 251, 259 and 260 contain the trademark/trade name “(MATRIGEL®). 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, 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 “a gelatinous protein mixture extracted from Engelbreth-Holm-Swarm (EHS) mouse sarcomas cells” and, accordingly, the identification/description is indefinite.
iii. The rest of claims are indefinite as depending from an indefinite claim.
Claim Rejections - 35 USC § 112
6. The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 243-270 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
Claims 243-270 are drawn to a method of producing corneal endothelial cells (CEC), comprising (a) contacting neural crest stem cells (NCSCs) with a genus of at least one DKK2 agonist or at least one PDGFB agonist or a combination thereof to induce differentiation of the NCSCs into CEC.
The claims encompass using a genus of at least one DKK2 agonist or at least one PDGFB agonist or a combination thereof to induce differentiation of the NCSCs into CEC.
Applicant has not disclosed sufficient species for the broad genus of LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists.
The specification only describes a defined cornea medium comprising both PDGFB and DKK2 to induce differentiation of NCSCs into CECs on p. 60-62 of the instant specification.
However, the claims are not limited to the agents or medium or conditions or method set forth above but also encompasses using structurally and functionally undefined agents, medium and conditions to induce differentiation of NCSC into CEC.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant is in possession of and what Applicant is claiming.
M.P.E.P. § 2163 instructs:
An invention described solely in terms of a method of making and/or its function may lack written descriptive support where there is no described or art-recognized correlation between the disclosed function and the structure(s) responsible for the function. . . .
An applicant may show possession of an invention by disclosure of drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole. . . .
An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics.”
This standard has not been met in this case. From the specification, Applicant is in possession of a method of inducing neural crest stem cells to differentiate into corneal endothelial cells by a defined cornea medium comprising PDGFB and DKK2 as on p. 60-62 of the instant specification. However, Applicant is not in possession of use of other structurally and functionally undefined DKK2 agonists and/or other molecules recited in claims 243 or as described on p. 32-34 of the specification for inducing differentiation of NCSC CECs in an undefined medium.
The specification provides no identification of any particular portion of the structure that must be conserved for the claimed factors, PDGFB agonists or DKK2 agonists or for culture media or conditions. The instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of PDGFB agonists and/or DKK2 agonists including structurally and functionally undefined LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists. There is no description of the conserved regions which are critical to the function of the claimed genus. There is no description of the sites at which variability may be tolerated and there is no information regarding the relation of structure of other PDGF agonists and/or DKK2 agonists including structurally and functionally undefined LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists to the function of the combination of PDGFB and DKK2 and corneal medium used in the specification. Furthermore, the prior art does not provide compensatory structural or correlative teachings sufficient to enable one of skill to isolate and identify what other PDGFB agonists and/or DKK2 agonists including LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists might be.
Applicant fails to provide sufficient guidance as to whether PDGFB agonists or DKK2 agonists including LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists can be used in the claimed method since a single amino acid change can change or abolish the binding ability or activity of a molecule or protein. For example, a substitution of lysine residue by glutamic acid at position 118 of acidic fibroblast growth factor results in a substantial loss of its biological activity including the binding ability to heparin and its receptor (Burgess et al. J of Cell Bio. 1990, 111:2129-2138, as in IDS). Although many amino acid substitutions are possible in any given protein, the position of where such amino acid substitutions can be made is critical for maintaining the function of a protein; i.e. only certain positions can tolerate conservative substitutions without changing the relationship of three dimensional structure and function of the protein (col 2, p. 1306, Bowie et al. Science, 1990, 247:1306-1310, as in IDS). Although the specification outlines art-recognized procedures for producing and the screening method, this is not adequate guidance as to the nature of active PDGFB agonists and/or DKK2 agonists including LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists that may be constructed, but is merely an invitation to the artisan to use the current invention as a starting point for further experimentation.
Even if an active or binding site were identified in the specification, they may not be sufficient, as the ordinary artisan would not immediately recognize that an active or binding site must assume the proper three-dimensional configuration to be active because conformation is dependent upon surrounding residues; i.e. substitution of non-essential residues can often destroy activity. In addition to a core determinant sequence, the protein-protein interaction also relies on the flanking or noncontiguous residues (see p. 445 the second column, first paragraph, Pawson et al. 2003, Science 300:445-452). The optimal binding motif for a domain is not necessarily suitable for physiological or in vivo interaction. The predictive data always need to be validated by actual analyses in cells (see p. 445, the third column, second paragraph, Pawson et al. 2003, Science 300:445-452, as in IDS). Applicant fails to teach what other structures/amino acid sequences can or cannot be included or changed in the claimed genus of PDGFB agonists and/or DKK2 agonists including LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists in order to preserve the activity of the combination of PDGFB and DKK2 polypeptide in inducing differentiation of NCSCs
into CECs in a defined medium. In addition, neither the specification nor the prior art teaches what other factors or agonists can act as PDGFB in combination with DKK2 in a corneal medium and thus can be used in the claimed method. Applicant
fails to provide sufficient guidance as to what other structures/characteristics are
required for the claimed factors or PDGFB agonists or DKK2 agonists in order to
maintain the activity of PDGFB in combination with DKK2 in inducing differentiation of NCSCs into CECs in a defined medium.
Since the common characteristics/features of other PDGFB agonists and/or DKK2 agonists including LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists are unknown, a skilled artisan cannot envision the functional correlations of the claimed genus with the claimed invention. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the genus of PDGFB agonists and/or DKK2 agonists including LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists.
Based on MPEP § 2161.01 and §2163, “to satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116”.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of PDGFB agonists and/or DKK2 agonists including LRP5/6 antagonists, Kremen antagonists, Wnt modulator, Casein Kinase 1-7 ß catenin antagonists, LEF/TCF transcription factor members modulators, Wnt proteins, nucleic acids encoding Writ proteins, Axin antagonists or APC antagonists for inducing differentiation of NCSC into CECs, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483.
Therefore, the claimed method has not met the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115). Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, ¶ 1 "Written Description" Requirement. See MPEP § 2161.01 and 2163.
Claim Rejections - 35 USC § 103
7. 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 243, 245, 248, 250-260, 262-265 and 269 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Nishida (JP2009-268433, published Nov 19, 2009, as in IDS)-English translated version in view of Hoppenreijs et al. (IOVS 1994; 35: 150-161, as in IDS) and evidentiary references: Hayashi et al. (US9347041, as in IDS), Chiambaretta et al. (Mol. Vis. 2004; 10:901-9, as in IDS), Fan et al. (Mol. Vis. 2011; 17:469-480, as in IDS) and Shimmura et al. (US9347042, as in IDS).
Claim 243, 245, 248, 250-260, 262-265 and 269 are drawn to a method of producing corneal endothelial cells (CEC), comprising:(a) contacting neural crest stem cells (NCSCs) with at least one DKK2 agonist, at least one PDGFB agonist or a combination thereof to induce differentiation of NCSCs into CEC, wherein the at least one DKK2 agonist including DKK2, Dkk 1; Dkk 3; Dkk 4; LRP5/6 antagonists; Kremen antagonists; Soggy; secreted frizzled related proteins (Frzb); Wnt inhibitor factor (WIF); a Wnt modulator; Casein Kinase 1-7 ß catenin antagonists; LEF/TCF transcription factor members modulators; IWR; pyrvinium; ICG-001; PKF115-584; IWP; Antl.4Br/Ant 1.4C1 ; Niclosamide; apicularen; bafilomycin; XAV939; NSC668036; 2,4-diamino-quinazoline; Quercetin; Wnt proteins, nucleic acids encoding Wnt proteins, LiC1, Axin
antagonists; APC antagonists; norrin; R-spondin2; (hetero)arylpyrimidines; IQ1; BIO(6-
bromoindirubin-3'-oxime); 2-amino-4-[3,4- (methylenedioxy)benzyl-amino]-6-(3-
methoxyphenyl)pyrimidine; a Wnt modulator; WAY-316606; QS11; SB-216763; SB-
216763; DCA; and any combination thereof and wherein the at least one PDGFB agonist includes PDGFB, PDGFAA polypeptide, a nucleic acid encoding PDGFAA, PDGFAB polypeptide, a nucleic acid encoding PDGFAB, Phorbol 12-myristate 13-acetate (PMA), VEGF, and any combination thereof.
Nishida (JP2009-268433) teaches a method of generating corneal endothelial cells (CEC) from neural crest stem cells (NCSCs), comprising contacting NCSCs with a TGF-beta2 at a concentration of 1-50ng/ml (see p. 5, [0032]-[0033]; [0035]-[0037], p. 6, [0043]-[0044]; [0047]-p.8-0058]; p. 9, [0064]-[0070], in particular). Nishida teach that the CECs produced from NCSCs express one or more markers for CECs including type VIII collagen (COL8A1), N-cadherin, ZO-1, Na+/Ke+ ATPase, which meets the limitation recited in claim 264 (see [0041], [0056], [0058]-[0061], [0063], [0070],in particular).The CECs disclosed by Nishida expressing Na+/Ke+ ATPase, ZO-1,, KLF13, AQP1, Collagen VIII, SLC16A3, CFTR, NBC1, CA2, AE2/SCL4A2, SCL16A1, CA12, CA4, FoxC1 and do not express vWF and CD31 recited in claim 264 are also evidenced by Hayashi et al. (see col.5, lines 30-41; col.6, lines 25-62 in US9347041), Chiambaretta ((see p. 906, 1st paragraph, lines 3-10; p. 904, table 2 and, figure 2; Chiambaretta et al., Mol. Vis. 2004; 10:901-9 ), Fan et al (see p. 472, 2nd col., 4th paragraph to p.473; 1st col., 2nd paragraph; p. 475, 1st col.-2nd col. Figures 5-7; Fan et al., Mol. Vis. 2011; 17:469-480), Shimmura et al. ((see co. 12, lines 7-14; col. 11, lines 20-40, col. 13-20, examples 1-7 in US9347042) and Lee et al. (Nature Protocols, 2010;5: 688-701).
Hayashi teaches that the in vitro differentiated CECs produced from NCSCs are characterized by expression of collagen VIII, ZO-1, Na+/K+ ATPase, and at initial differentiation stage, the in vitro differentiated CECs produced from NCSCs also express and retain neural crest markers including PITX2, FOXC1 for differentiation of CECs (see col.5, lines 30-41; col.6, lines 25-62). Chiambaretta teaches that the in vitro differentiated human CECs express different KLFs and KLF13 is uniquely expressed in human CECs (see p. 906, 1st paragraph, lines 3-10; p. 904, table 2 and, figure 2). Fan teaches that the in vitro differentiated human CECs express COL4A2, FLK1, ZO-1, N-cadherin, Connexin 43, integrin av/b5 and different membrane transport protein genes including AQP1, ATP1A1, VDAC2, VDAC3, ClC2, ClC3, NBC1, and CFTR but not vWF and keratin 12 (see p. 472, 2nd col., 4th paragraph to p.473; 1st col., 2nd paragraph; p. 475, 1st col.-2nd col. Figures 5-7). Shimmura teaches that CECs produced from induced pluripotent stem cell (iPSC)-derived NCSCs express Na+/K+ ATPase (ATP1A1), ZO-1, SLC4A4, Col8A2, Pitx2, N-cadherin (see co. 12, lines 7-14; col. 11, lines 20-40, col. 13-20, examples 1-7). Thus, the Nishida’s in vitro differentiated CECs produced from NCSCs express Na+/K+ ATPase, ZO-1, FOXC1, collagen VIII, CFTR, KLF13, AQP1, SLC4A4 evidenced by Ju et al. (see p.1, abstract; p. 1-5, figures 3-6; p. 8; the reference of Ju is a post filing reference to show the undiscovered properties).
Nishida teaches that the differentiating NCSCs are passaged and is about 3 days as in claim 252-254 (see [0048]-[0049]), The NCSCs disclosed by Nishida express NCSC markers including p75(NGFR), Sox 2, Sox9, Musashi, Wnt1, Twist, Snail, nestin, ABCG2 as in claims 262-263 (see [0036], in particular). The NCSCs disclosed by Nishida express Sox10, AP2, HNK1, Pax3, PAX7 and p75(NGFR) as evidenced by Lee et al. (see p. 693). Further, the NCSCs disclosed by Nishida are produced from embryonic stem cells as in claim 269 (see [0025], [0028], [0030], [0032], in particular). Nishida also teaches that harvesting the CEC as a sheet of CEC as in claim 261, or cultured on a substrate and released onto a carrier or a matrix including collagen I as in claims 250 and 259 (see [0043]-[0044]; [0055], in particular) and that CEC are human CEC (see p. 9, [0021], in particular). Nishida teaches contacting cells with a cell dissociation buffer including non-enzymatic or EDTA, mechanical dissociation, or optical dissociation as in claims 255-257 (see [0047]-[0049]). Nishida teaches harvest CECs as a sheet of CEC having a cell density of at least 5000 cells/mm2 as related to claims 261 because Nishida teaches that 1x105 cells/ml were plated in a culture dish, which is at least 5000 cells/mm2 (see [0043]-[0044], in particular).
But Nishida does not teach at least one PDGFB agonist as in claims 243, 245, 248 and 258.
Hoppenreijs et al. teach that PDGF including PDGFBB, PDGFAA and PDGFAB at concentrations of 10ng/ml, 75ng/ml can promote proliferation and survival of corneal endothelial cells as in claims 243 and 248 (see p. 150; p. 152-156, table 4, in particular).
A person of ordinary skill in the art would have recognized that selecting and applying the known PDGFBB, PDGFAA or PDGFAB and the known technique disclosed by Hoppenreijs to the Nishida’s method would have yielded the predictable result of producing CECs differentiated from NCSCs and resulted in an improved method because PDGFBB, PDGFAA and PDGFAB at concentrations of 10ng/ml, 75ng/ml have been shown to promote proliferation and survival of corneal endothelial cells as taught by Hoppenreijs
Using and including PDGFBB, PDGFAA or PDGFAB in the Nishida’s method would generate CECs and expand application of the Nishida’s method, and would increase production of CECs for therapeutic patient’s purposes and treatment of corneal disorders using CECs. Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teaching of Hoppenreijs with the teaching of Nishida to select and apply the known PDGFBB, PDGFAA or PDGFAB and the known technique disclosed by Hoppenreijs to the Nishida’s method and yield the predictable result of producing CECs differentiated from NCSCs because PDGF agonists including PDGFBB, PDGFAA and PDGFAB polypeptides have been shown to promote proliferation and survival of corneal endothelial cells. The selection of a known material based on its suitability for its intended use supports a prima facie obviousness determination. It is obvious to use a known material for its intended use in a known method taught by the prior art. Note that
“The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)”. See MPEP § 2144.07.
“Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so. In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006)” See MPEP § 2143. 01-I.
Claim Rejections - 35 USC § 103
8. Claims 243-244, 246 and 258 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Nishida et al. (JP2009-268433-English translated version) in view of Hoppenreijs et al. (1994), and evidentiary references: Hayashi et al. (US9347041), Chiambaretta et al. (2004), Fan et al. (2011) as applied to claims 243, 245, 248, 250-260, 262-265 and 269 above, and further in view of Mendlein et al. (US2012/0207744, published Aug 16, 2012, priority Mar 19, 2009, as in IDS).
Nishida and Hoppenreijs are set forth above but fail to teach a DKK2 agonist alone or in combination with a PDGF agonist as in claims 243-244, 246, and 258.
Mendlein et al. (US2012/0207744) teaches different agents that promote cell survival and differentiation of corneal endothelial cells including agents that modulates a Wnt pathway, Hedgehog pathway, a TGF-beta pathway, a receptor tyrosine kinase pathway, a Jak/STAT pathway and a Notch pathway including Dkk 1; Dkk 3; Dkk 4; LRP5/6 antagonists; Kremen antagonists; Soggy; secreted frizzled related proteins (Frzb); Wnt inhibitor factor (WIF); a Wnt modulator; Casein Kinase 1-7 ß catenin antagonist…PDGF, VEGF, FGF, Wnt/beta-catenin, which meets the limitations of DDK2 agonists as in claims 243-246, and 258 (see p. 2; [0024]; [0031]; [0055]; [0297-0298], in particular). Mendlein also teaches different dosages for the claimed DDK2 agonists (see [1210]-[1214], in particular). Mendlein teaches different biocompatible material including collagen, laminin, Matrigel ([1284]; [1287]-[1290]).
A person of ordinary skill in the art would have recognized that selecting and applying the known DKK2 agonist and the known technique disclosed by Mendlein to the method of Nishida and Hoppenreijs would have yielded the predictable result of producing CECs differentiated from NCSCs and resulted in an improved method because DDK2 agonists including Dkk 1; Dkk 3; Dkk 4; LRP5/6 antagonists; Kremen antagonists; Soggy; secreted frizzled related proteins (Frzb); Wnt inhibitor factor (WIF); a Wnt modulator; Casein Kinase 1-7 ß catenin antagonist…PDGF, VEGF, FGF, Wnt/beta-catenin have been shown to promote survival of CECs as taught by Mendlein and PDGF agonists including PDGFBB, PDGFAA and PDGFAB polypeptides have been shown to promote proliferation and survival of CECs as taught by Hoppenreijs.
Using and including a DDK2 agonist including Dkk 1; Dkk 3; Dkk 4; LRP5/6 antagonists; Kremen antagonists; Soggy; secreted frizzled related proteins (Frzb); Wnt inhibitor factor (WIF); a Wnt modulator; Casein Kinase 1-7 ß catenin antagonist…PDGF, VEGF, FGF, Wnt/beta-catenin alone or in combination with a PDGFB agonist including PDGFBB, PDGFAA or PDGFAB in the method of Nishida and Hoppenreijs would generate CECs and expand application of the method of Nishida and Hoppenreijs, and would increase production of CECs for therapeutic patient’s purposes and treatment of corneal disorders using CECs.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teaching of Mendlein with the teachings of Nishida and Hoppenreijs to select and apply the known DDK2 agonist including Dkk 1; Dkk 3; Dkk 4; LRP5/6 antagonists; Kremen antagonists; Soggy; secreted frizzled related proteins (Frzb); Wnt inhibitor factor (WIF); a Wnt modulator; Casein Kinase 1-7 ß catenin antagonist…PDGF, VEGF, FGF, Wnt/beta-catenin alone or in combination with a PDGFB agonist including PDGFBB, PDGFAA or PDGFAB and the known technique disclosed by Mendlein to t the method of Nishida and Hoppenreijs and yield the predictable result of producing CECs differentiated from NCSCs because DDK2 agonists including Dkk 1; Dkk 3; Dkk 4; LRP5/6 antagonists; Kremen antagonists; Soggy; secreted frizzled related proteins (Frzb); Wnt inhibitor factor (WIF); a Wnt modulator; Casein Kinase 1-7 ß catenin antagonist…PDGF, VEGF, FGF, Wnt/beta-catenin have been shown to promote survival of CECs as taught by Mendlein and PDGF agonists including PDGFBB, PDGFAA and PDGFAB polypeptides have been shown to promote proliferation and survival of CECs as taught by Hoppenreijs. Note that the selection of a known material based on its suitability for its intended use supports a prima facie obviousness determination. It is obvious to use a known material for its intended use in a known method taught by the prior art. Note that
“The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)”. See MPEP § 2144.07.
“Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so. In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006)” See MPEP § 2143. 01-I.
Claim Rejections - 35 USC § 103
9. Claims 259-260, 262-263 and 265-270 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Nishida et al. (JP2009-268433-English translated version) in view of Hoppenreijs et al. (1994) and Mendlein et al. (US2012/0207744) and evidentiary references: Hayashi et al. (US9347041), Chiambaretta et al. (2004), Fan et al. (2011), Shimmura et al. (US9347042) and Lee (2010) as applied to claims 243-246 248, 250-260, 262-265 and 269 above, and further in view of Lee et al. (Nat. Protocols, 2010; 5:688-701).
Nishida, Hoppenreijs and Mendlein are set forth above but do not teach culturing NCSCs on a matrix including different matrix and Matrigel or by contacting hPSCs including hESCs or hiPSCs with at least one SMAD inhibitor including Noggin and/or SB431542 as in claims 266-270.
Lee teaches a method of producing NCSCs from human pluripotent stem cells including hESCs and hiPSCs, comprising culturing hESCs or hiPSCs on Matrigel-coated or gelatin or laminin or fibronectin-coated peri-dish as in claims 259-260 (p.690-692; p. 699-700) at 10x103/cm2 in a KSR medium containing 10 µM SB431542 and 500 ng/ml Noggin (p. 692; p. 699-670) as in claims 265-268 to induce differentiation of hESCs or hiPSCs into NCSCs as in claims 267-270, and wherein the NCSCs express Sox10, AP2, HNK1, Pax3, PAX7 and p75(NGFR) as in claims 262-263 (see p.693-700).
A person of ordinary skill in the art would have recognized that selecting and applying the known method of producing NCSCs by culturing hPSCs including hESCs and hiPSCs on a matrix including gelatin, laminin, fibronectin and Matrigel in a medium comprising SMAD inhibitor including Noggin and SB31542 and the known technique disclosed by Lee to the method of Nishida, Hoppenreijs and Mendlein would have yielded the predictable result of producing NCSCs from human pluripotent stem cells including hESCs and hiPSCs and resulted in an improved method because Lee teaches a method of producing NCSCs from human pluripotent stem cells including hESCs and hiPSCs, comprising culturing hESCs or hiPSCs on Matrigel-coated or gelatin or laminin or fibronectin-coated peri-dish in a medium containing SB431542 and Noggin to induce differentiation of hESCs or hiPSCs into NCSCs.
Using the known method of producing NCSCs by culturing hPSCs including hESCs and hiPSCs on a matrix including gelatin, laminin, fibronectin and Matrigel in a medium comprising SMAD inhibitor including Noggin and SB31542 in the method of Nishida, Hoppenreijs and Mendlein would more efficiently produce NCSCs for generation of CECs and expand application of the method of Nishida, Hoppenreijs and Mendlein and would increase production of CECs for therapeutic patient’s purposes and treatment of corneal disorders using CECs.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine the teaching of Lee with the teachings of Nishida, Hoppenreijs and Mendlein to select and apply the known method of producing NCSCs by culturing hPSCs including hESCs and hiPSCs on a matrix including gelatin, laminin, fibronectin and Matrigel in a medium comprising SMAD inhibitor including Noggin and SB31542 to the method of Nishida, Hoppenreijs and Mendlein because Lee has taught a method of producing NCSCs by culturing hPSCs including hESCs and hiPSCs on a matrix including gelatin, laminin, fibronectin and Matrigel in a medium comprising SMAD inhibitor including Noggin and SB31542. Note that "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose. [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980); see also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) and Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992). See MPEP § 2144.06.
Further, "The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. V. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945)". See MPEP § 2144.07.
"Obviousness can be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so. In re Kahn, 441 F.3d 977, 986, 78 USPQ2d 1329, 1335 (Fed. Cir. 2006)" See MPEP § 2143. 01-I.
Claim Rejections - 35 USC § 103
10. Claims 250-251 and 261 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Nishida et al. (JP2009-268433-English translated version) in view of Hoppenreijs et al. (1994), Mendlein et al. (US2012/0207744) and Lee et al. (2010), and evidentiary references: Hayashi et al. (US9347041), Chiambaretta et al. (2004), Fan et al. (2011) as applied to claims 243, 245, 248, 250-260, 262-263 and 265-270 above, and further in view of Shimmura et al. (US9347042) and Koizumi et al. (US2010/0209402, published Aug 19, 2010, as in IDS).
Nishida, Hoppenreijs, Mendlein and Lee are set forth above but do not teach CECs on different matrix as recited in claims 250-251 or a cell density that is exactly identical to the claimed range of at least 6000 cells/mm2 as in claim 261.
Shimmura teaches that a method of efficiently producing CECs from ES-derived NCSCs or induced pluripotent stem cell (iPSC)-derived NCSCs (Examples 1-7), comprising culturing the ESC/iPSC-derived NCSCs in a differentiation induction medium containing a GSK3 inhibitor and retinoic acid, and further containing one or more TGFb2, insulin and a ROCK inhibitor (see abstract; col.), wherein the CECs produced from iPSC-derived NCSCs express Na+/K+ ATPase (ATP1A1), ZO-1, SLC4A4, Col8A2, Pitx2, N-cadherin as recited in claims 264 (see co. 12, lines 7-14; col. 11, lines 20-40, col. 13-20, examples 1-7). Shimmura also teaches harvesting a sheet of the CECs at a density range of 500-600,000 cells/cm2 (i.e. 50-60000 cells/mm2) or 2000-8000 cells/mm2 or 4000-6000 cells/mm2 (see co. 8, lines 16-23; lines 55-60; col. 16-22, example 1) or at a density range of 1x104-5x106 cells/cm2 or 1x105-1x106 cells/cm2 (i.e. 1x103-5x105cells/mm2 or 1x104-1x105cells/mm2) (see co. 12, lines 7-14; col. 11, lines 20-40, col. 13-20, examples 1-7), which meets the limitation recited in claim 261.
Koizumi (US2010/0209402) teaches a method of promoting adhesion of a corneal endothelial cell, comprising contacting an effective amount of a Rho kinase inhibitor with a target or corneal endothelial cell in need of promotion of adhesion of the corneal endothelial cell and harvesting and preparing a sheet of CECs having a cell density of about 1-2x106 cells/ml, or 2000 cells per well on a 96 well plate, or 20000 cells per well on a 12-well plate, 10000 cells per well on a 48-well plate, which is within or overlaps with the claimed density of at least 6000 cells/mm2 recited in claims 261 (see abstract; [0053], [0057], [0065], [0067], [0069], [0078], [0080], [0094], in particular). Koizumi also teaches different types of substrate/matrix for supporting a sheet of CECs including collagen I/IV, fibronectin, laminin, extracelluar matrix or polymer materials derived from collagen, gelatin, cellulose or amniotic membrane as recited in claims 250-251 and 259-260 (see [0048]-[0053]; [0055], in particular).
A person of ordinary skill in the art would have recognized that selecting and applying the the known cell density of at least 6000 cells/mm2, the known substrate/matrix including collagen I/IV, fibronectin, laminin, extracelluar matrix or polymer materials derived from collagen, gelatin, cellulose or amniotic membrane for supporting a sheet of CECs and the known technique disclosed by Shimmura and Koizumi to the method of Nishida, Hoppenreijs, Mendlein and Lee would have yielded the predictable result of culturing NCSCs on the known substrate/matrix including collagen I/IV, fibronectin, laminin, extracelluar matrix or polymer materials derived from collagen, gelatin, cellulose or amniotic membrane for generating a sheet of CECs having a cell density of at least 6000 cells/mm2 and resulted in an improved method because Shimmura teaches producing CECs from ESC/iPSC-derived NCSCs at a density range of 500-600,000 cells/cm2 (i.e. 50-60000 cells/mm2) or 2000-8000 cells/mm2 or 4000-6000 cells/mm2 or at a density range of 1x104-5x106 cells/cm2 or 1x105-1x106 cells/cm2 (i.e. 1x103-5x105cells/mm2 or 1x104-1x105cells/mm2), and Koizumi teaches using different substrate/matrix including collagen I/IV, fibronectin, laminin, extracelluar matrix or polymer materials derived from collagen, gelatin, cellulose or amniotic membrane for promoting and generating a sheet of CECs having a cell density of about 1-2x106 cells/ml, or 2000 cells per well on a 96 well plate, or 20000 cells per well on a 12-well plate, 10000 cells per well on a 48-well plate, which is within or overlaps with the claimed density of at least 6000 cells/mm2.
Using and including the known cell density of at least 6000 cells/mm2, the known substrate/matrix including collagen I/IV, fibronectin, laminin, extracelluar matrix or polymer materials derived from collagen, gelatin, cellulose or amniotic membrane for supporting a sheet of CECs in the method of Nishida, Hoppenreijs, Mendlein and Lee would generate CECs having a cell density of at least 6000 cells/mm2 and expand application of the method of Nishida, Hoppenreijs, Mendlein and Lee, and would increase production of CECs for therapeutic patient’s purposes and treatment of corneal disorders using CECs.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to combine the teachings of Shimmura and Koizumi with the teachings of Nishida, Hoppenreijs, Mendlein and Lee to select and apply the known CECs having a cell density of at least 6000 cells/mm2, the known substrate/matrix including collagen I/IV, fibronectin, laminin, extracelluar matrix or polymer materials derived from collagen, gelatin, cellulose or amniotic membrane for supporting a sheet of CECs and the known technique disclosed by Shimmura and Koizumi to the method of Nishida, Hoppenreijs, Mendlein and Lee because Shimmura teaches Koizumi has taught a composition comprising a sheet of CECs having a cell density that is either within or overlaps with the claimed range.
Note that in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists” See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) & MPEP 2144.05-I. In addition, “a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985)” See MPEP 2144.05-I.
Double Patenting
11. 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 243-270 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No.9752118. Although the claims at issue are not identical, they are not patentably distinct from each other because the method recited in claims 1-9 of the US9752118 (the ‘118 patent) anticipates the method recited in instant claims of the instant application.
The claims 1-9 of the ‘118 patent claims a method of producing CECs comprising contacting ES cells with Noggin and SB431542 to induce differentiation of ES cells into NCSCs, and contacting NCSCs with DKK2 with PDGFB to induce differentiation of NCSCs into CECs that express Na+/K+ ATPase, ZO-1, KLF13, AQP1, Collagen VIII, SLC16A3, CFTR, NBC1, Carbonic anhydrase II (CA2), Anion exchanger 2 (AE2/SCL4A2), Solute Carrier Family 16 A1 (SCL16A1), SCL16A3, Carbonic anhydrase 12 (CA12), Carbonic Anhydrase 4 (CA4), cystic fibrosis transmembrane conductance regulator (CFTR) and transcription factor FoxC1, which is a species of instant claims. Therefore, claims 243-270 of the instant Application are not patentably distinct from claims 1-9 of the ‘118 patent because instant claims 243-270 are anticipated by claims 1-9 of the ‘118 patent
Conclusion
12. NO CLAIM IS ALLOWED.
13. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Gage et al. (Invest. Ophthalmol. Vis. Sc. 2005; 46:4200-4208,as in IDS) teach that transcription factors PITX2 and FOXC1 are expressed in neural crest-derived cells (p. 4202, 2nd col., 2nd paragraph; p. 4207).
Zhang et al. (Stem cells and Develop. 2014; 23: DOI:10.1089/scd.2013.0510, as in IDS) teaches human corneal endothelial cells derived from human embryonic stem cells express N-cadherin and transcription factors FOXC1 and Pitx2 (see abstract; p.1340, abstract; p. 1343, 2nd col.to p. 1346, figures 1-3; p. 1351).
Maxson et al. (US2012/0219535, published Aug 30, 2012, priority Oct 2, 2009, as in IDS) teaches that neural crest stem cells (NCSCs) can differentiate into corneal endothelial cells (CEC) (paragraphs [0010]-[0013]).
14. Any inquiry of a general nature or relating to the status of this general application should be directed to the Group receptionist whose telephone number is (571) 272-1600.
Papers relating to this application may be submitted to Technology Center 1600, Group 1649 by facsimile transmission. The faxing of such papers must conform with the notice published in the Official Gazette, 1096 OG 30 (November 15, 1989). Should applicant wish to FAX a response, the current FAX number for Group 1600 is (571) 273-8300.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Chang-Yu Wang whose telephone number is (571) 272-4521. The examiner can normally be reached on Monday-Thursday from 7:00 AM to 5:30 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeffrey Stucker, can be reached at (571) 272-0911.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Chang-Yu Wang
October 3, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
