DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06-17-2025 has been entered.
Applicant's amendments to the claims and arguments filed on 06-17-2025 have been received and entered. Claims 1, 3, 7, have been amended. Claims 12-29 have been canceled. Claims 33-36 have been added. Claims 1-11, 30-36 are pending.
Election/Restrictions
Applicant’s election of Group I, directed to claims 1-11 and 30-32 in the reply filed on 05-20-2024 is acknowledged. Applicant’s election of species a costimulatory molecule, combination of CD80 and CD86, adenovirus, placenta, human is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 2, 4-6 were previously withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected subject matter , there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05-20-2024.
Upon further consideration, election of species requirement for “a human leukocyte antigen (HLA)” and “polypeptide associated with fibrosis” are hereby withdrawn. Claim 2 and 6 are hereby rejoined with the elected species. Claims 4-5 remain withdrawn from consideration.
Claims 1, 2, 3, 6, 7-11, 30-36 are under consideration.
Priority
This application is a 371 of PCT/US19/66575 filed on 12/16/2019 that claims priority from US provisional 62/780,289 filed on 12/16/2018.
New-Claim Rejections - 35 USC § 112
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 1, 3, 7-11, 30-36 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “reduction in the expression of a polynucleotide sequence encoding an immunogenic component” which renders the claim vague and indefinite. It is unclear the “reduction in the expression of a polynucleotide sequence” is as compared with what control/standard. As a result, it is unclear how much gene expression for one of the recited markers will satisfy the claim’s limitations regarding ‘reduced’ expression.
Claim 1 recites “a polypeptide associated with an increase in the expression of human leukocyte antigens” and “a polypeptide associated with fibrosis”. The specification of the claimed invention does not provide any instruction/definition for how “a polypeptide” can be “associated with an increase in the expression of human leukocyte antigens” or “associated with fibrosis”. There is no definition for the term “associated with”. It is unclear if the polypeptide is directly or indirectly “associated with an increase in the expression of human leukocyte antigens” or “associated with fibrosis”. It is unclear what the mechanism or the identity of the polypeptide can be to fit in the limitation of “associated with”.
Claim 10 recites “mammalian tissues are further derived from umbilical cord, foreskin, skin, omentum, adipose tissue, and/or bone marrow.”. Claim 10 indirectly depends from claim 1 which recite “placental fibroblast cell”. It is unclear how placental fibroblast cell can be derived from other tissue than placenta.
Claims 3, 7-11, 30-36 are included in the rejection because they directly or indirectly depend from the rejected claims. Appropriate correction is required.
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 1, 3, 7-11, 30-36 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.
Claims are directed to an isolated engineered placental fibroblast cell comprising a reduction in the expression of a polynucleotide sequence encoding an immunogenic component selected from the group consisting of a) a human leukocyte antigen (HLA); b) a costimulatory molecule, wherein the costimulatory molecule comprises CD80 and CD86; c) an adhesion molecule; d) a polypeptide ‘associated with’ an increase in the expression of human leukocyte antigens; e) a polypeptide ‘associated with’ fibrosis; and f) a combination thereof.
In analyzing whether the written description requirement is met for the genus claim, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics, specific features and functional attributes that would distinguish different members of the claimed genus. 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. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. Amer. Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (Fed. Cir. 1997). Possession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was "ready for patenting" such as by the disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the applicant was in possession of the claimed invention. See, e.g., Pfaffv. Wells Elecs., Inc., 525 U.S. 55, 68, 119 S.Ct. 304,312, 48 USPQ2d 1641, 1647 (1998); Eli Lilly, 119 F.3d at 1568, 43). USPQ2d at 1406; Amgen, Inc. v. Chugai Pharm., 927 F.2d 1200, 1206, 18 USPQ2d 1016, 1021 (Fed. Cir. 1991).
The claims encompass a genus of any means of reduction (via any regulatory pathway/signal transduction pathway with any regulatory components or any technique) in the expression of a polynucleotide sequence encoding an immunogenic component selected from the group consisting of (a) any human leukocyte antigen (HLA); (b) a costimulatory molecule, wherein the costimulatory molecule comprises CD80 and CD86; (c) any adhesion molecule; (d) any polypeptide ‘associated with’ an increase in the expression of human leukocyte antigens; (e) any polypeptide ‘associated with’ fibrosis.
a. The claims encompass a genus of any reduction in the expression of a human leukocyte antigen (HLA) can be achieved by epigenetic silencing (DNA methylation, histone deacetylation), microRNAs (post-transcriptional regulation), transcriptional regulators etc.: Nie et al (Carcinogenesis, Volume 22, Issue 10, October 2001, Pages 1615–1623, Doi:10.1093/carcin/22.10.1615) teach DNA hypermethylation is a mechanism for loss of expression of the HLA class I genes in human (title), and their results indicate that HLA class I gene expression was frequently down-regulated in ESCC at both the protein and mRNA levels and that hypermethylation of the promoter regions of the HLA-A, -B and - C genes is a major mechanism of transcriptional inactivation (Abstract). Manaster et al (PLoS ONE 7(3): e33395. doi:10.1371/journal.pone.0033395) teach MiRNA-Mediated Control of HLA-G Expression and Function (title) and MiR-148a and miR-152 down-regulate HLA-G expression (See Figure 3, page e33395). Meissner et al (PNAS | August 3, 2010 | vol. 107 | no. 31, doi: 10.1073/pnas.1008684107) teach NLR family member NLRC5 is a transcriptional regulator of MHC class I genes (title) and , they showed that the IFN-γ–induced up-regulation of MHC class I requires NLRC5, because knockdown of NLRC5 specifically impaired the expression of MHC class I (HLA-A,HLA-B, and HLA-C), and loss of CIITA in humans and mice results in the severe reduction of only MHC class II expression ((HLA-DRA, -DQA, and -DPA)) (see abstract). Thus, claims encompass known or yet to be identified regulatory molecule that may result in reduction in the expression of a human leukocyte antigen (HLA).
b. The claims encompass a genus of any reduction in the expression of a costimulatory molecule, wherein the costimulatory molecule comprises CD80 and CD86. The expression of costimulatory molecule such as CD80 and CD86 can be regulated to be downregulated by factors such as interleukin-10, TGF-β etc. : Schülke (Front. Immunol. 9:455. doi: 10.3389/fimmu.2018.00455) teaches treatment of DC with IL-10 significantly downregulated surface expression of MHC I, MHC II, CD80, CD86, and programmed death ligand 2 (PD-L2) (Figure 2A) (Page 11, left column, 1st para.). Wallet et al (Clinical Medicine & Research Volume 3, Number 3: 166-175, ) teach thar TGF-β1 inhibits upregulation of the costimulatory molecules CD83 and CD86 in humans42 and CD80 and CD86 in mice,43 thereby reducing the efficacy of dendritic cells to stimulate T lymphocytes (Page 169, right column, 2nd para.). Thus, claims encompass known or yet to be identified regulatory molecule that may result in reduction in the expression of a costimulatory molecule comprises CD80 and CD86.
c. The claims encompass a genus of any reduction in the expression of a genus of any adhesion molecules: Prozialeck et al (Pharmacology & Therapeutics 114 (2007) 74–93, doi:10.1016/j.pharmthera.2007.01.001) teaches that cell adhesion molecules are integral cell–membrane proteins that maintain cell–cell and cell–substrate adhesion and in some cases act as regulators of intracellular signaling cascades. In the kidney, cell adhesion molecules, such as the cadherins, the catenins, the zonula occludens protein-1 (ZO-1), occludin and the claudins are essential for maintaining the epithelial polarity and barrier integrity that are necessary for the normal absorption/excretion of fluid and solutes (Abstract). Steinbacher et al (Cellular and Molecular Life Sciences (2018) 75:1393–1409, Doi:10.1007/s00018-017-2729-0) teach Junctional adhesion molecule‑A: functional diversity through molecular promiscuity (title), Cell adhesion molecules (CAMs) of the immunoglobulin superfamily (IgSF) regulate important processes such as cell proliferation, differentiation and morphogenesis (Abstract). For example, Junctional adhesion molecule-A (JAM-A) is a member of the JAM family of cell–cell adhesion receptors (page 1394, left column, last para.). Thus, the claims encompass known or as yet unknown adhesion molecules whose expression is reduced by any mechanism.
d. The claims encompass a genus of any reduction in the expression of any polypeptide associated with an increase in the expression of human leukocyte antigens. There are wide ranges of factors that increase HLA expression such as interferons such as IFN-γ, toll-like receptor ligands, cytokines and inflammatory mediators etc. Rodríguez et al (BMC Cancer 2007, 7:34 doi:10.1186/1471-2407-7-34) teach distinct mechanisms of loss of IFN-gamma mediated HLA class I inducibility (title). They observed two distinct mechanisms of loss of IFN-γ inducibility of HLA class I antigens in two melanoma cell lines and suggested that loss of HLA class I induction in ESTDAB-004 cells results from a defect in the earliest steps of the IFN-γ signaling pathway due to absence of STAT-1 tyrosine-phosphorylation, while absence of IFN-γ-mediated HLA class I expression in ESTDAB-159 cells is due to epigenetic blocking of IFN-regulatory factor 1 (IRF-1) transactivation (Abstract). Hou et al (Immunity. 2008 August 15; 29(2): 272–282. doi:10.1016/j.immuni.2008.05.016.) teach microbial TLR ligands can induce DCs to mature, a response characterized by up-regulation of surface MHC-peptide complexes (page 2, 1st para), and both CpG and CpG/DOTAP induced increased expression of CD86, CD40 and to a lesser extent, class II MHC molecules in splenic cDCs, but the response to CpG/DOTAP was much stronger (Figure 4A) (Page 5). Propper et al (Clinical Cancer Research, Vol. 9, 84–92, January 2003, ) teach low-dose IFN-γ induces tumor MHC expression in metastatic malignant melanoma (title), and IFN- γ induced significant up-regulation of surrogate markers of monocyte activation (serum neopterin) and class I up-regulation (serum b-2-microglobulin) in most patients (Abstract). Thus, the claims encompass the reduction of expression for genes encoding an enormous genus of polypeptides ‘associated with’ an increase in the expression of human leukocyte antigens whose reduced gene expression can be mediated a number of different ways.
e. The claims encompass a genus of any reduction in the expression of any polypeptide associated with fibrosis: There are wide ranges of factors that are associated with fibrosis: growth factors such as TGF-β, cytokine, extracellular matrix structural proteins etc. Trojanowska (The Open Rheumatology Journal, 2012, 6, (Suppl 1: M1) 70-71) teaches mediators of fibrosis (title) and stated that while we are learning more about the pathways that contribute to fibrosis, it would be important to integrate this new information with the large body of existing knowledge on the profibrotic mediators, especially Transforming Growth factor β (TGF β). TGF β is one of the most potent inducers of extracellular matrix and has long been considered to be a principal mediator of fibrosis (Page 70, left column, 1st para.). Mu et al (Oper Tech Orthop. 2010 June 1; 20(2): 110–118. doi:10.1053/j.oto.2009.10.003) teach additional molecular factors have also been identified as important mediators in fibrosis, including: Th2-type cytokines (IL-4, IL-5, IL-13, IL-21), chemokines (MCP-1, MIP-1β), angiogenic factors (VEGF), growth factors (CTGF, PDGF, TNF-α), peroxisome proliferatoractivated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin-angiotensin-aldosterone system (Angiotensin II/ANG II) [25]. Also, TGF-β2 and endothelin (ET) were found to mediate fibrosis in situations like subepithelial layer of the airways when brought on by chronic asthma (Page 3, 2nd para.). Williams et al (PNAS | August 25, 2020 | vol. 117 | no. 34 | 20753–20763, Doi: 10.1073/pnas.2004281117) found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1. Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing (Abstract). Thus, the instant claims also encompass the downregulated expression of an enormous genus of genes encoding polypeptides that are ‘associated with’ fibrosis in a subject, where the downregulated expression can be mediated in a number of different ways.
The specification of the claimed invention only teaches limited information/guidance for the claimed limitation: “the polypeptide sequence(s) that are reduced in expression comprise one or more immunogenic proteins, for example, as one or more human leukocyte antigens (HLA), one or more costimulatory molecules, one or more adhesion molecules, one or more polypeptides associated to increase HLA expression, and/or one or more polypeptides associated with the onset and continuous progression of fibrosis.” (see [0010], page 3). The only working example related to “reduction in the expression of a polynucleotide sequence” of the claims is example 2 which only discuss “Foreskin fibroblasts were purchased from ATCC …… To cut out the HLA gene, the gene editing of beta 2 microglobulin (B2M) and class II MHC transactivator (CIITA) were knocked out using the CRISPR/Cas9 genome editing system….” ([0101]-[0102, page 34-35]). The claimed invention as a whole is not adequately described if the claims require essential or critical elements which are not adequately described in the specification and which is not conventional in the art as of applicants effective filing date. Possession may be shown by actual reduction to practice, clear depiction of the invention in a detailed drawing, or by describing the invention with sufficient relevant identifying characteristics such that a person skilled in the art would recognize that the inventor had possession of the claimed invention. Pfaff v. Wells Electronics, Inc., 48 UsPQ2d 1641, 1646 (1998). There is no evidence that any reduction in the expression of a polynucleotide sequence encoding an immunogenic component as claimed would be similarly functional.
The specification lacks sufficient variety of species to reflect this variance in the genus showing contemplated biological activity of reduction in the expression of a polynucleotide sequence encoding an immunogenic component as claimed. Thus, it is reasonable to conclude that the specification does not provide sufficient descriptive support for the enormous genus of different engineered fibroblasts embraced by the rejected claims.
The skilled artisan cannot envision the detailed genus of immunogenic components as claimed other than those described in the specification, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of making an isolated engineered placental fibroblast cell. 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. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) and Amgen lnc. v.Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Thus, it is reasonably concluded that the instant disclosure does not describe a sufficient number of specific embodiments that meet the functional limitations of the rejected claims to demonstrate possession of the broadly claimed genus of engineered placental fibroblasts.
New- Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
The following rejection is directed to those embodiments encompassed by alternative item (e) of claim 1 (i.e., a polypeptide associated with fibrosis) :
Claims 1, 6, 8, 9, 10 and 11 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Ohmaru-Nakanishi et al. (The American Journal of Pathology, Vol. 188, No. 3, March 2018, Doi: 10.1016/j.ajpath.2017.11.008) as evidenced by Lehner et al (Obstet Gynecol. 2001 Jun;97(6):965-70, doi: 10.1016/s0029-7844(01)01131-0.).
Regarding to claims 1, 6, 8, Ohmaru-Nakanishi et al teach “fibrosis in preeclamptic placentas is associated with stromal fibroblasts activated by the transforming growth factor-b1 signaling pathway” (Title). Ohmaru-Nakanishi et al teach Knockdown of TGFBR1 Gene Expression in Placental Fibroblasts: A validated siRNA for transforming growth factor beta receptor 1 (TGFBR1) (103324; Thermo Fisher Scientific) was used to compare with negative control siRNA (AM4611; Thermo Fisher Scientific) (See page 686, right column, 2nd para). Additionally, placental fibroblast expresses human telomerase reverse transcriptase (hTERT) as evidenced by Lehner et al who teach “Localization of Telomerase hTERT Protein and Survivin in Placenta” (title) : Lehner et al teaches the telomerase hTERT protein was localized to the trophoblastic cells of developing and molar placental tissue and other components of the placental villi, including nucleated hematologic precursors of first-trimester placenta and scattered villous stromal fibroblasts (Page 968, right column, last para.).
Regarding to claims 9 and 11, Ohmaru-Nakanishi et al teach tissue blocks of a cross section of placenta (of pregnant Japanese women) located halfway between the cord insertion point and the lateral edge were dissected, and chorion and decidua were removed soon after deliveries and saved for histologic analysis and isolation of fibroblasts (page 684, right column, 1st para.)
Regarding to claim 10, Ohmaru-Nakanishi et al teach Activated fibroblasts might originate from tissue fibroblasts, endothelial cells, epithelial cells, pericytes, or bone marrow-derived cells (page 684, left column 1st para.)
Thus, claims 1, 6, 8, 9, 10 and 11 are anticipated by Ohmaru-Nakanishi et al.
New- Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The following rejection is directed to those embodiments encompassed by alternative (a) of claim 1 (i.e., a human leukocyte antigen (HLA):
Claims 1-2, 7-8, 9, 10, 11 and 30, 31, 32, 34, 35, 36 are rejected under 35 U.S.C. 103 as being unpatentable over Gregory et al (Pub. No.: US 2017/0216358 A1, Pub. Date: Aug. 3, 2017) in view of Tom et al . (Pub. No .: US 2020/0281981 A1, provisional application No. 61/338,489 , filed on Feb. 18 , 2010) as evidenced by Lehner et al (Obstet Gynecol. 2001 Jun;97(6):965-70, doi: 10.1016/s0029-7844(01)01131-0.).
Claim interpretation:
In the remark filed on 06-17-2025, Applicant point to [0007] of specification of the claimed invention on page 2 to state that claims 1 and 3 are currently amended finding support at least in ¶ [0007] (describing that fibroblasts can be extracted, i.e. isolated, from a source) (Remarks page 5). Additionally, the instant specification also teach fibroblasts are extracted from sources with lower immunogenicity (e.g. placental fibroblasts, etc.) (see [0079], page 25). However, there is no guidance for the term “isolated” or the degree of purity of “extracted” fibroblasts are extracted from sources. Thus, isolation/extraction of fibroblasts are interpreted broadly with different degree of purity of the extracted/islolated cells.
Additionally, there is no definition of the term “Fibroblast” in the specification of the claimed invention. The specification of the claimed invention only stated that “ wherein the cells are fibroblasts of any type ….. the fibroblasts may be of any kind, including placenta, umbilical cord, foreskin, skin, omentum,
adipose tissue, and/or bone marrow, or derivatives thereof, for example” ([0078], page 25). The term “Fibroblast” is interpreted according to the teaching of prior art.
Regarding to claim 1-2, 8, and 31, 34, Gregory et al teach “methods and compositions for modulating the expression of a HLA locus” (Abstract), and “FIG. 7 shows ZFN-mediated elimination of HLA-A expression on human ESC …….Clones (5230, 5255, 5258) were chosen with loss of HLA-A expression and differentiated into fibroblasts” ([0032], page 4). Any of the modified stem cells described herein (modified at the HLA locus/loci) may then be differentiated to generate a differentiated (in vivo or in vitro) cell descended from a stem cell as described herein ([0019], page 2).
Gregory et al do not teach placental fibroblast cell. However, Tom et al cure the deficiency.
Tom et al teach “Provided herein is a placental product comprising an immune-compatible amniotic membrane …...” (Abstract). According to the present invention , a placental product comprises native therapeutic cells of the amniotic membrane. The cells comprise one or more of stromal cells ,
MSCs , fibroblasts, and epithelial cells ([0108], page 6). Additionally, placental fibroblast expresses human telomerase reverse transcriptase (hTERT) as evidenced by Lehner et al who teach “Localization of Telomerase hTERT Protein and Survivin in Placenta” (title) : Lehner et al teaches the telomerase hTERT protein was localized to the trophoblastic cells of developing and molar placental tissue and other components of the placental villi, including nucleated hematologic precursors of first-trimester placenta and scattered villous stromal fibroblasts (Page 968, right column, last para.).
It is noted that Gregory et al teach “the materials and methods of the invention can be used in the treatment, prevention or amelioration of graft-versus-host-disease” ([0161], page 17), “prevent rejection of these organs in humans and increase the chances for successful transplantation” ([0164], page 17) and “the complete HLA class I knock out feasible for human application by avoiding the introduction of immunogenic transgenes” ([0188], page 21). Additionally, Tom et al teach immune-compatible amniotic membrane …...” (Abstract); “a placental product of the present invention is used in a tissue graft procedure.” ([0241], page 11); “selectively depleted of immunogenicity” ([0035], page 2). Tom et al also teach and “ Selective depletion of immunogenicity ” or “ selective depletion of immunogenic cells or factors ” or “ selective depletion ” means a placental product that retains live therapeutic cells and / or retains therapeutic efficacy for the treatment of tissue injury yet is free, substantially free, or depleted of at least one of immune cell type (e.g., CD14+ macrophages , trophoblasts, and /or vascular -tissue derived cells ) and/or immunogenic factor that are otherwise present in a native placenta or amniotic membrane ([0063], page 3). Thus, a person of ordinary skill in the art would combine the above references and modify/knock out HLA genes in placental cell such as fibroblasts for reducing immunogenicity.
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the method of Gregory et al by using a placental product comprises fibroblasts as taught by Tom et al as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Tom et al provide explicit advantage of using a method of manufacture of placental membranes, resulting in low immunogenicity of the final products ([0305], page 19). Tom et al also teach Example 26: placental tissues enhance cell migration and wound healing ([0356], page 29). Tom et al also stated that “These data demonstrate that the methods of manufacture according to the present invention produce placental products with unexpectedly superior levels of factors that promote wound healing .” ([0363], page 29). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Tom et al were successful in generation of placental product that comprises fibroblasts for therapeutic use with substantially free, or depletion of immunogenic factor.
Regarding to claim 7, Gregory et al teach that the methods typically comprise (a) cleaving an endogenous HLA gene or HLA regulator gene in an isolated cell (e.g., T-cell or lymphocyte) using a nuclease (e.g., ZFN or TALEN) or nuclease system such as CRISPR/Cas with an engineered crRNA/tracr RNA such that the HLA or HLA regulator gene is inactivated ([0021], page 2)
Regarding to claims 9, 10, 11 Gregory et al teach “the disclosed methods and compositions can be used in any type of cell including …. animal cells, vertebrate cells, mammalian cells and human cells….,” ([0158], page 16-17). Stem cells are isolated for transduction and differentiation using known methods. For example, stem cells are isolated from bone marrow cells ([0152], page 16).
Regarding to claim 30, Tom et al teach the present invention provides a pharmaceutically
acceptable placental product ([0027], page 2). Additionally, Gregory et al teach pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition ([0157], page 16).
Regarding to claim 32, Tom et al teach “a method of treating a subject comprising administering a placental product to the subject … the step of administering comprises applying the placental product to a wound …” ([0037], page 2).
Regarding to claim 35, Tom et al teach that instant membrane product, which provides necessary angiogenic and anti -inflammatory growth factors was introduced in an effort to improve outcomes of patients with chronic skin ulceration at -risk for amputation ([0367], page 30), and depletion of allogeneic donor tissue macrophages decreases the level of inflammatory cytokine secretion and tissue immunogenicity ([0308], page 19).
Regarding to claim 36, Tom et al teach cells were isolated from the placental membranes using enzymatic digestion ([0277], page 14), and the cells comprise one or more of stromal cells , MSCs , fibroblasts, and epithelial cells ([0108], page 6).
Claims 3 and 33 are rejected under 35 U.S.C. 103 as being unpatentable over Gregory et al (Pub. No.: US 2017/0216358 A1, Pub. Date: Aug. 3, 2017) in view of Tom et al . (Pub. No .: US 2020/0281981 A1, provisional application No. 61/338,489 , filed on Feb. 18 , 2010) as evidenced by Lehner et al (Obstet Gynecol. 2001 Jun;97(6):965-70, doi: 10.1016/s0029-7844(01)01131-0.) as applied to claims claims 1-2, 7-8, 9, 10, 11 and 30, 31, 32, 34, 35, 36 above, and further in view of Nolan et al (Am J Respir Crit Care Med Vol 177. pp 301–308, 2008, DOI: 10.1164/rccm.200703-515OC on November 11, 2007 ).
The teachings of Gregory et al, Tom et al, Lehner et al above are incorporated herein in their entirety.
The above references do not teach the costimulatory molecule further comprises cluster of differentiation 40 (CD- 40), interleukin 12 (IL-12), or combination thereof. Nolan et al cure the deficiency.
Regarding to claim 3 and 33, Nolan et al teach inhibition of individual costimulatory cascades has been used successfully in animals and more recently in humans to partially control inflammation in autoimmune disease and graft rejection. (Page 301, right column, last para). Nolan et al also teach CD40 and CD80/86 act synergistically to regulate inflammation and mortality in polymicrobial sepsis (Title), and CD40/80/86-/- mice showed a reduction in plasma and BAL fluid IL-12 at 6 hours (see Figure E1D) and 18 hours (Figure 3) (Page 304, left column, 1st para.). The reduction in IL-12 further implicates a specific role for CD40 in the regulation of IL-12 and helper T-cell type 1 cytokine production in sepsis (Page 306, right column, 1st para.)
It is noted that, in claim 33, the phrase “wherein the reduction in the expression of the polynucleotide comprising a co-stimulatory molecule is mediated by CRISPR/Cas9” is interpreted as product by process as directed to an activated stem cell. See MPEP 2113: [E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted).
Therefore, it would have been prima facie obvious for a person of ordinary skill in the art before the effective filing date of the rejected claims to combine the teachings of prior art to modify the placental fibroblast cell as taught by the above references by inhibiting expression of CD40 and IL-12 to control graft rejection as taught by Nolan et al, as instantly claimed, with a reasonable expectation of success. Said modification amounting to combining prior art elements according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to do so because Nolan et al teaches that combined inhibition of CD40 may improve mortality in sepsis (abstract), and improves survival in polymicrobial sepsis: Nolan et al reported that CD40-/- mice have delayed mortality and attenuation of IL-6, IL-10, and IL-12 production (Page 303, left column, 3rd para.). One of ordinary skill in the art would have had a reasonable expectation of success in doing so because Nolan et al was successful in create CD40-/- mice with attenuation IL-12 production that have a normal lifespan and breeding pattern (Page 302, left column, 3rd para., Methods).
Conclusion
No claim is allowed.
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/KHOA NHAT TRAN/Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632