DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 21-35 are pending.
Claims 30-31 and 34-35 are withdrawn.
Claims 21-29 and 32-33 are under examination.
Election/Restrictions
Applicant’s election without traverse of the following species:
Activation Type: exposing the fibroblasts to one or more cytokines (claims 26-33)
Cytokine Type: IL-1 (claims 28-29)
in the reply filed on 18th, November, 2025 is acknowledged. Claims 21-29 and 32-33 encompass the elected species.
The requirement is still deemed proper and is therefore made FINAL.
Claims 30-31 and 34-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Objection to Abstract
The abstract of the disclosure is objected to because it contains legal phraseology ("means" lines 1 and 4) Correction is required. See MPEP § 608.0l(b).
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Objections to Specification
The disclosure is objected to because of the following informalities: Para. [0007], line 3 has a sentence which ends with two periods.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
Improper Markush
Claims 23-24 are rejected on the basis that they contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
Regarding claim 23, the Markush grouping of “CD73, CD90, CD56, SSEA3, SSEA4, Tra-1-60, Tra-1-81, Tra-2-54, HLA class I, CD13, CD44, CD49b, CD105, aminopeptidase N, hyaluronic acid-binding receptor, collagen/laminin-binding integrin alpha 2, OCT4, NANOG, SOX-2, and a combination thereof” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The listed markers are structurally distinct with distinct functions. Additionally, different combinations of the markers as claimed represent structurally and functionally distinct cell types.
Regarding claim 24, the Markush grouping of “CD14, CD34, CD45, HLA Class II, and a combination thereof” is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: The listed markers are structurally distinct with distinct functions. Additionally, different combinations of “lacking” the markers as claimed represent structurally and functionally distinct cell types.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(b)
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 21-29 and 32-33 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 21 recites “the step of subjecting a subject to a system under conditions that allow for secretion of one or more regenerative factors from cells in the system” and claim 21 also recites the system comprises “tubing connecting at least one of the bioreactor(s), at least one of the selectively permeable membrane(s), and the subject in order to circulate fluid from the subject to the bioreactor.” However, “subjecting a subject to a system” is broad and does not necessarily require connecting the system to the subject, and although “tubing connecting at least one of the bioreactor(s), at least one of the selectively permeable membrane(s), and the subject in order to circulate fluid from the subject to the bioreactor,” is claimed as part of the system, it is not claimed as an active method step and is therefore unclear whether an active method step of connecting the tubing to the subject is required and it is also unclear whether a connection between the subject and the system is required.
Regarding claim 21, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) is considered indefinite, since the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). Note the explanation given by the Board of Patent Appeals and Interferences in Ex parte Wu, 10 USPQ2d 2031, 2033 (Bd. Pat. App. & Inter. 1989), as to where broad language is followed by "such as" and then narrow language. The Board stated that this can render a claim indefinite by raising a question or doubt as to whether the feature introduced by such language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Note also, for example, the decisions of Ex parte Steigewald, 131 USPQ 74 (Bd. App. 1961); Ex parte Hall, 83 USPQ 38 (Bd. App. 1948); and Ex parte Hasche, 86 USPQ 481 (Bd. App. 1949). In the instant case claim 22 recites the broad recitation “subjecting a subject to a system”, and the claim also recites “tubing connecting at least one of the bioreactor(s), at least one of the selectively permeable membrane(s), and the subject” which is the narrower statement of the range/limitation. Since the claim does not clearly set forth that the subjecting a subject to a system comprises connecting the tubing, it is unclear what the metes and bounds of the claim encompass.
By nature of their ultimate dependency on claim 21, claims 22-29 and 32-33 are also rejected because they do not clarify the issue.
Claim 24 recites the negative limitation “the fibroblasts lack one or more surface markers” together with a list of alternatives “one or more surface markers selected from the group consisting of CD 14, CD34, CD45, HLA Class II, and a combination thereof” The presence of a negative limitation preceding a list of alternatives makes the scope of the claim indefinite because it is unclear whether the negative limitation applies to all the listed alternatives, or whether it applies to the options in the alternative.
Claim 25 recites “The method of claim 22, wherein the method comprises the step(s) of:
(a) culturing fibroblasts in an undifferentiated state for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,
14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25 or more days;
(b) culturing the fibroblasts from step (a) in the presence of one or more factors selected from
the group consisting of nerve growth factor, bFGF, dibutryl cAMP, IBMX, retinoic acid,
exendin-4, and a combination thereof; and
(c) activating the fibroblasts.” It is unclear how the method steps of claim 25 are related to the method of claim 21, upon which claim 25 ultimately depends for the following reasons. First, claim 25 recites the method comprises the step(s) of: (a) (b) and (c) which recite fibroblasts that are not required by claim 21 and are also not claimed as the fibroblasts of claim 22 because they are not claimed as “the fibroblasts” of claim 22. Therefore, the steps of claim 25 read on a method of culturing fibroblast that appears distinct and unrelated from the method of claims 21 and 22 upon which it depends. Additionally, claim 25 recites the method “comprises the step(s) of:” while claim 21, upon which claim 25 ultimately depends, already states the method steps comprised by the method which drawn to subjecting a subject to a system and are distinct from those claimed in claim 25. It is unclear how methods of culturing fibroblasts that are not required by claim 21 or claim 22 can further limit these claims which are drawn to a method of subjecting a subject to a system. There is no nexus between the culturing method steps of claim 25 and the claims upon which it depends and therefore the metes and bounds of the claim are indefinite.
Generally, when the claims are indefinite, vague or unclear, they cannot be construed without speculation or conjecture; therefore, the indefinite claims are not treated on the merits with respect to prior art. See In re Steele, 305 F.2d 859, 862 (CCPA 1962) (A prior art rejection cannot be sustained if the hypothetical person of ordinary skill in the art would have to make speculative assumptions concerning the meaning of claim language.); see also In re Wilson, 424 F.2d 1382, 1385 (CCPA 1970) ("If no reasonably definite meaning can be ascribed to certain terms in the claim, the subject matter does not become obvious-the claim becomes indefinite."). Notwithstanding Steele, the Office has made every attempt to construe the claims in what the Office believes is the intent of the Applicants in the interest of compact prosecution.
Claim Interpretation
Due to the 112b issues identified above, for the sake of compact prosecution, the claims identified with 112 issues above are being examined against the prior art and double-patenting as follows:
In light of the specification, the instant method is interpreted to require that the step of “subjecting a subject to a system” comprises connecting the subject to the system with the tubing of the system (see Figure 1).
Regarding claim 25, in light of the specification, it appears that the steps of claim 25 are intended to apply to the cell of the system of claim 22 which is a fibroblast derived from tissues comprising skin, heart, blood vessels, bone marrow, skeletal muscle, liver, pancreas, brain, adipose tissue, placenta, and/or foreskin, and to be done as a step before the cells are used in the system (see para. [0048] “in some embodiments of the disclosure, the cells are cultured in the presence of one or more cytokines in order to activate the cell for use in the system” and “the cells are cultured in the presence of factor(s) that may include nerve growth factor, bFGF, dibutryl cAMP, IBMX, retinoic acid, exendin-4, or other factors either alone or in combination that are useful for producing the desired activated cells” para. [0046]). For the sake of compact prosecution, instant claims are interpreted accordingly to encompass the method further comprising the steps of (a), (b), and (c) as claimed applied to the “the cells are fibroblasts that are derived from tissues comprising skin, heart, blood vessels, bone marrow, skeletal muscle, liver, pancreas, brain, adipose tissue, placenta, and/or foreskin” of claim 22 before they are added to the system.
Claim Rejections - 35 USC § 102
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.
Claim 21 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yarmush et al. (EP 2578081 A2; see IDS filed 9th, May, 2024; henceforth “Yarmush”).
Regarding claim 21, Yarmush discloses an extracorporeal method comprising the step of subjecting a subject (“subjects with liver disease” para. [0007]; see also para. [0012-0019, 0025, 0029, 0031-0033]; “Methods of Treatment” para. [0053-0054]) to a system under conditions that allow for secretion of one or more regenerative factors from cells in the system (extracorporeal perfusion; para. [0230]),
wherein the system comprises:
(a) at least one bioreactor comprising cells,
(b) a selectively permeable membrane (i.e., plasma separator), and
(c) tubing connecting the bioreactor, the selectively permeable membrane, and the subject in order to circulate fluid from the subject to the bioreactor (extracorporeal circuit; para. [0010, 0228-0230], Figure 20; pg. 5, 25; Example 15; Claim 1).
Regarding the preamble of claim 21, the preamble merely states, the purpose or intended use of the invention (producing regenerative factors), rather than any distinct definition of any of the claimed invention’s limitations and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). Furthermore, Yarmush discloses all the structural limitations of the claimed method above and therefore the method of Yarmush would produce regenerative factors as claimed. Lastly, Yarmush discloses the method includes MSCs in the extracorporeal circuit, which are known to produce regenerative factors, and liver serologies were improved in animals treated with the method, evidencing regenerative factors were produced (Example 15).
Regarding the limitation of “conditions that allow for secretion of one or more regenerative factors from cells in the system” of claim 21, as stated above, Yarmush discloses the conditions of the method of extracorporeal perfusion (para. [0230]; Example 15). The conditions disclosed in Example 15 of Yarmush improved liver serologies (para. [0230]; Figures 21A-B), and resulted in a demonstrated hepatoprotective effect as shown by the reduction in biochemical markers of hepatocyte death (para. [0230]; Figure 21C: Example 15), and therefore the conditions disclosed by Yarmush allow for secretion of one or more regenerative factors from cells in the system.
Accordingly, Yarmush anticipates instant claim.
Claims 21-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pittenger et al. (WO-2015/160952-A1; see IDS filed 9th, May, 2024; henceforth “Pittenger”) as evidenced by Denu et al. (Acta Haematol. 2016;136(2):85-97. Epub 2016 May 18.; henceforth “Denu”).
Regarding claim 21, Pittenger discloses an extracorporeal method comprising the step of subjecting a subject to a system (“The apparatus or device may be implanted or present outside the body of a subject (extracorporeal) and attached to an in vivo organ or tissue via tubing or catheters” pg. 9 lines 13-15; see also abstract; pg. 12- 13 “Apparatus for cellular therapy” and “a method of treating a medical condition by establishing a fluid communication between the apparatus or device of the first aspect of the invention and an organ, tissue or subject” pg. 5 lines 10-12), wherein the system comprises:
at least one bioreactor (bag, apparatus or device) comprising cells (MSCs pg. 2 line 37; pg. 3 line 10; pg. 5 lines 8-9, 15-16; pg. 8 lines 9, 19-21, 23-24, 26, 29, 32; pg. 9 line 10; pg. 12 lines 35 and 37; pg. 13 lines 28, 33, 36, 40; pg. 14 lines 30, 35-36; pg. 15 lines 3, 5-6, 17-18, 30, 32; pg. 15-18 “Immortalized cells of the invention”; pg. 20 lines 21, 23-26, 28,30, 32-33, 39; pg. 21 line 20; pg. 22 lines 6, 34, 36-37 and 39; pg. 23 lines 9, 14; Example 1; Figures 2A, 3A-B, 4-6; claims 6, 11, 50, 54, 112, 116); see also pg. 2 lines 31-40 and claims 5-10 which cite alternative embodiments of “cells of the lung, heart, liver, bladder, brain, nervous system tissue, blood vessels, skin, eye structures, gut, bone, muscle, ligament, cartilage, esophagus, pancreas, intestines, gallbladder, bile duct, fallopian tubes, ovaries, prostate, spinal cord, spleen, stomach, testes, thymus, thyroid, trachea, ureter, urethra, uterus, or fat” and “embryonic stem cells, induced pluripotent stem cells (IPS), hematopoietic stem cells, intestinal stem cells, osteoblastic stem cells, mesenchymal stem cells (MSCs), multipotent adult progenitor cells (MAPCs), neural stem cells, epithelial stem cells, bone stem cells, cardiac myocyte progenitor stem cells, skin stem cells, skeletal stem cells, muscle stem cells, endothelial stem cells, endothelial progenitor cells, umbilical cord stem cells, adipose stem cells, placental stem cells, placental-derived multipotent stem cells, or liver stem cells”)
at least one selectively permeable membrane (porous material/matrix material; pg. 2 lines 16, 23; pg. 3 line 16; pg. 7 line 14; pg. 8 lines 10, 16, 19, 23-24, 37’; pg. 9 line 10; pg. 10 line 22; pg. 12 line 21; pg. 13 line 13, 16, 20, 33, 39; pg. 14 line 3-6, 9, 12-14, 25, 30, 36, 39; pg. 19 line 36; Figure 2A; claims 1, 15, 20, 77 and 82; or hollow fibers ; pg. 3 line 17; pg. 7 lines 16 and 20; pg. 13 line 39; pg. 14 lines 3, 9, 12-14; claims 15, 77), and
tubing comprising connecting at least one of the bioreactor(s), at least one of the selectively permeable membrane(s), and the subject in order to circulate fluid from the subject to the bioreactor (see Figure 7D).
Regarding the preamble of claim 21, the preamble merely states, the purpose or intended use of the invention (producing regenerative factors), rather than any distinct definition of any of the claimed invention’s limitations and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). Furthermore, Pittenger discloses all the structural limitations of the claimed method above and therefore the method of Pittenger would produce regenerative factors as claimed. Lastly, Pittenger discloses the method includes MSCs in the bioreactor, which produce regenerative factors (“Bioactive factors produced by stem cells” pg. 20).
Regarding the limitation of “conditions that allow for secretion of one or more regenerative factors from cells in the system” of claim 21, as stated above, Pittenger discloses “the apparatus or device of the invention transfers the therapeutic substances or bioactive factors produced by the resident cells in the apparatus or device to the recipient damaged organs or tissues” (pg. 20 “Bioactive factors produced by stem cells”) and therefore the method is under “conditions that allow for secretion of one or more regenerative factors from cells in the system” as claimed.
Regarding claim 22, as stated above, Pittenger discloses the cells are mesenchymal stem cells (MSCs; pg. 2 line 37; pg. 3 line 10; pg. 5 lines 8-9, 15-16; pg. 8 lines 9, 19-21, 23-24, 26, 29, 32; pg. 9 line 10; pg. 12 lines 35 and 37; pg. 13 lines 28, 33, 36, 40; pg. 14 lines 30, 35-36; pg. 15 lines 3, 5-6, 17-18, 30, 32; pg. 15-18 “Immortalized cells of the invention”; pg. 20 lines 21, 23-26, 28,30, 32-33, 39; pg. 21 line 20; pg. 22 lines 6, 34, 36-37 and 39; pg. 23 lines 9, 14; Example 1; Figures 2A, 3A-B, 4-6; claims 6, 11, 50, 54, 112, 116). Pittenger discloses the MSCs are positive for CD73, CD90, and CD105, and negative for hematopoietic markers (e.g., CD34) (pg. 16 lines 26-27), and specifically Pittenger discloses the MSCs are bone marrow MSCs (pg. 16 line. 24).
Regarding claim 22, although Pittenger is silent to the cells being fibroblasts derived from foreskin, Denu evidences fibroblasts derived from the foreskin are phenotypically Indistinguishable from bone marrow mesenchymal stem cells (pg. 2 3rd para “Conclusions—Based on currently accepted definitions for cultured human MSCs and fibroblasts, we could not find any immunophenotypic property that could make a characteristic distinction between MSCs and fibroblasts” and pg. 7 last para. “fibroblast strains express all the cell surface markers of the ISCT consensus criteria that are used to define MSCs”; see also Title; abstract; conclusion and “Culture of Fibroblasts” pg. 4). Denu evidences all the fibroblasts tested were positive for CD73, CD90, and CD105; negative for CD14, CD34, CD45, CD19; and HLA-DR, similar to MSCs (Figure 2; pg. 6).
Therefore, regarding claim 22, because Denu evidences the MSCs from the bone marrow disclosed by Pittenger are structurally indistinguishable from fibroblasts derived from foreskin, the MSCs from the Bone marrow of Pittenger meet the structural requirements of Instant claims.
Lastly, regarding claim 22, it is noted that “derived from” is product-by process language with respect to the cells of the instant method. Applicant is reminded that product-by process claims are not limited by the manipulation of the recited steps, only the structure implied by the steps. “[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) (see MPEP 2113). In the instant case, as discussed above, Denu evidences the bone marrow MSCs of Pittenger are structurally indistinguishable from fibroblasts derived from foreskins and therefore the bone marrow MSCs of Pittenger meet the required structure of instant claims.
Regarding claims 23-24, further to the discussion of claims 21-22 above, as stated above, Pittenger discloses the bone Marrow MSCS, which are structurally indistinguishable from foreskin-derived fibroblasts, are positive for CD73, CD90, and CD105 (instant claim 23) and negative for hematopoietic markers (e.g., CD34) (pg. 16 lines 26-27) (instant claim 24).
Accordingly, Pittenger anticipates instant claims.
Examiner’s Remark
As stated above, claims 22-24 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pittenger et al. (WO-2015/160952-A1; see IDS filed 9th, May, 2024; henceforth “Pittenger”) as evidenced by Denu et al. (Acta Haematol. 2016;136(2):85-97. Epub 2016 May 18.; henceforth “Denu”) on the grounds that the bone Marrow MSCS disclosed by Pittenger are structurally indistinguishable from the foreskin-derived fibroblasts required by instant claims for the reasons stated above (see rejection under 35 U.S.C. 102 above). Because instant claims require “fibroblasts that are derived from” foreskin, which is product-by process language, the bone Marrow MSCS disclosed by Pittenger appear to meet all the structural requirements of instant claims and therefore the preponderance of the evidence is that these cells meet instant claim limitations.
For the sake of compact prosecution, claims 22-24 are also rejected under 35 U.S.C. 103 as being unpatentable over Pittenger et al. (WO-2015/160952-A1; see IDS filed 9th, May, 2024; henceforth “Pittenger”) in view of Denu et al. (Acta Haematol. 2016;136(2):85-97. Epub 2016 May 18.; henceforth “Denu”) because the foreskin-derived fibroblasts of Denu appear to also be an obvious alternative to the bone Marrow MSCs of Pittenger (see rejection under 35 U.S.C. 103 below).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 22-24 are rejected under 35 U.S.C. 103 as being unpatentable over Pittenger et al. (WO-2015/160952-A1; see IDS filed 9th, May, 2024; henceforth “Pittenger”) in view of Denu et al. (Acta Haematol. 2016;136(2):85-97. Epub 2016 May 18.; henceforth “Denu”).
The teachings of Pittenger above are hereby incorporated in their entirety.
Regarding claim 22, further to the discussion of claim 21 above, as stated above, Pittenger discloses the cells are mesenchymal stem cells (MSCs; pg. 2 line 37; pg. 3 line 10; pg. 5 lines 8-9, 15-16; pg. 8 lines 9, 19-21, 23-24, 26, 29, 32; pg. 9 line 10; pg. 12 lines 35 and 37; pg. 13 lines 28, 33, 36, 40; pg. 14 lines 30, 35-36; pg. 15 lines 3, 5-6, 17-18, 30, 32; pg. 15-18 “Immortalized cells of the invention”; pg. 20 lines 21, 23-26, 28,30, 32-33, 39; pg. 21 line 20; pg. 22 lines 6, 34, 36-37 and 39; pg. 23 lines 9, 14; Example 1; Figures 2A, 3A-B, 4-6; claims 6, 11, 50, 54, 112, 116). Pittenger discloses the MSCs are positive for CD73, CD90, and CD105, and negative for hematopoietic markers (e.g., CD34) (pg. 16 lines 26-27), and specifically Pittenger discloses the MSCs are bone marrow MSCs (pg. 16 line. 24).
However, regarding claim 22, Pittenger is silent to using fibroblasts derived from foreskin with the method.
Nevertheless, regarding claim 22, Denu teaches fibroblasts derived from the foreskin are phenotypically Indistinguishable from bone marrow mesenchymal stem cells (pg. 2 3rd para “Conclusions—Based on currently accepted definitions for cultured human MSCs and fibroblasts, we could not find any immunophenotypic property that could make a characteristic distinction between MSCs and fibroblasts” and pg. 7 last para. “fibroblast strains express all the cell surface markers of the ISCT consensus criteria that are used to define MSCs”; see also Title; abstract; conclusion and “Culture of Fibroblasts” pg. 4). Denu teaches all the fibroblasts tested were positive for CD73, CD90, and CD105; negative for CD14, CD34, CD45, CD19; and HLA-DR, similar to MSCs (Figure 2; Supplemental Figure 1; pg. 6).
Therefore, regarding claim 22, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method of Pittenger, and simply substitute the known prior art element of the fibroblasts derived from foreskin of Denu for the bone Marrow MSCs of Pittenger to obtain the predictable result of an extracorporeal method for treating conditions. One of ordinary skill would have been motivated to do so as taught by Denu, because Denu teaches fibroblasts derived from the foreskin are phenotypically Indistinguishable from bone marrow mesenchymal stem cells (pg. 2 3rd para “Conclusions—Based on currently accepted definitions for cultured human MSCs and fibroblasts, we could not find any immunophenotypic property that could make a characteristic distinction between MSCs and fibroblasts” and pg. 7 last para. “fibroblast strains express all the cell surface markers of the ISCT consensus criteria that are used to define MSCs”; see also Title; abstract; conclusion and “Culture of Fibroblasts” pg. 4) and therefore they should be reasonably interchangeable with the bone marrow MSCs of Pittenger. Regarding the reasonable expectation of success, Pittenger evidences the method with bone marrow MSCs as discussed above. Because the fibroblasts derived from foreskin of Denu are phenotypically indistinguishable from the MSCs of Pittenger, they would be expected to also be usable in the claimed method.
Regarding claims 23-24, further to the discussion of claims 21-22 above, as stated above, Denu teaches the human foreskin derived fibroblasts were positive for CD73, CD90, and CD105 (instant claim 23); negative for CD14, CD34 and CD45 (Figure 2; Supplemental Figure 1; pg. 6).
Hence, the claimed invention as a whole was prima facie obvious.
Claims 25-29 and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Pittenger et al. (WO-2015/160952-A1; see IDS filed 9th, May, 2024; henceforth “Pittenger”) as evidenced by Denu et al. (Acta Haematol. 2016;136(2):85-97. Epub 2016 May 18.; henceforth “Denu”) view of Baddoo et al. (J Cell Biochem. 2003 Aug 15;89(6):1235-49.; henceforth “Baddoo”) and Redondo-Castro et al. (Stem Cell Res Ther. 2017 Apr 17;8(1):79.; henceforth “Redondo-Castro”).
The teachings of Pittenger and Denu above are hereby incorporated in their entirety.
Regarding claim 25, further to the discussion of claims 21-22 above, although Pittenger teaches using bone marrow MSCs in the method as cells, which are structurally indistinguishable from fibroblasts derived from foreskin, as discussed above, Pittenger is silent to steps of (a) culturing the cells in an undifferentiated state and (b), culturing the cells from step (a) in the presence of bFGF.
Nevertheless, regarding claim 25, Baddoo teaches a method of preparing bone marrow MSCs comprising the steps of (a) culturing the cells in an undifferentiated state for 3 days (“cultured at 378C with 5% CO2 in a humidified chamber for 72 h” Materials and Methods pg. 1236 col. 2) and (b) culturing the cells of step (a) in the presence bFGF (cultured 7 days in media with FGF2; pg. 1237 col. 1 1st para.). Baddoo teaches FGF2 stimulates growth of MSCs (pg. 1246 col. 1) and inhibits differentiation (pg. 1246 col. 2).
Therefore, regarding claim 25, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention and combine the known prior art elements of (a) culturing the cells in an undifferentiated state for 3 days and (b) culturing the cells of step (a) in the presence bFGF of Baddoo to obtain the predictable result of preparing MSCs for culture in the method of Pittenger. One of ordinary skill would have been motivated to do so as taught by Baddoo to prepare the MSCs for use after collection in step (a) and to stimulate growth and proliferation of the MSCs while inhibiting differentiation into an undesired cell type (pg. 1246). Regarding the reasonable expectation of success, Baddoo evidences a method of preparing bone marrow MSCs comprising the steps of (a) culturing the cells in an undifferentiated state for 3 days (“cultured at 378C with 5% CO2 in a humidified chamber for 72 h” Materials and Methods pg. 1236 col. 2) and (b) culturing the cells of step (a) in the presence bFGF (cultured 7 days in media with FGF2; pg. 1237 col. 1 1st para.).
However, regarding claims 25-29, Pittenger and Baddoo are silent to the step of activating the cell (instant claim 25), by exposing the cell to IL-1 cytokine in cell culture media (instant claims 26-29).
Nevertheless, regarding claims 25-29, Redondo-Castro teaches method steps of culturing bone Marrow MSCs including activating (priming) the cell (instant claim 25), by exposing the cell to IL-1 cytokine in cell culture media (instant claims 26-29) at a concentration of 1, 10, 50 or 100 ng/mL (instant claims 28-29) (Cell Treatments “MSC Priming” pg. 3 col. 1). Redondo-Castro teaches treatment of MSCs with IL-1α or IL-1β increased the secretion of trophic factors such as G-CSF (pg. 8 col. 1 Discussion). Redondo-Castro teaches that preconditioning treatments with IL-1 increased MSC secretion of anti-inflammatory mediators and trophic factors (pg. 9 col. 2 conclusions). Redondo-Castro teaches IL-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro (title).
Therefore, regarding claims 25-29, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Pittenger in view of Baddoo above, and combine the known prior art element of activating (priming) the cell MSC (instant claim 25), by exposing the cell to IL-1 cytokine in cell culture media (instant claims 26-29) at a concentration of 1, 10, 50 or 100 ng/mL (instant claims 28-29) of Redondo-Castro to obtain the predictable result of a primed MSC for use in the method. One of ordinary skill would have been motivated to do so as taught by Redondo-Castro to increase the secretion of anti-inflammatory mediators and trophic factors by the MSCs and to prime the mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype (pg. 9 col. 2 conclusions; Title). Regarding the reasonable expectation of success, Redondo-Castro evidences method steps of exposing MSCs to IL-1 cytokine in cell culture media at a concentration of 1, 10, 50 or 100 ng/mL (Cell Treatments “MSC Priming” pg. 3 col. 1).
Regarding claims 32-33, further to the discussion of claims 21-22 and 26 above, it is noted that the wherein clauses does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited ( “induces an increase in the expression of one or more complement inhibitory molecules” instant claim 32 and “the complement inhibitory molecules are selected from the group consisting of CD35, CD46, C4BP, CD55, Factor H, and a combination thereof”) . Therefore, the "wherein" clauses are not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Additionally, regarding claims 32-33, as stated above, Pittenger as evidenced by Denu in view of Baddoo and Redondo-Castro suggest all the active method steps of the instantly claimed method and therefore the claimed results of “an increase in the expression of one or more complement inhibitory molecules” (instant claim 32) where “the complement inhibitory molecules are selected from the group consisting of CD35, CD46, C4BP, CD55, Factor H, and a combination thereof” (instant claim 33), would naturally follow the recitation of the suggested active method steps.
Hence, the claimed invention as a whole was prima facie obvious.
Claims 25-29 and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Pittenger et al. (WO-2015/160952-A1; see IDS filed 9th, May, 2024; henceforth “Pittenger”) in view of Denu et al. (Acta Haematol. 2016;136(2):85-97. Epub 2016 May 18.; henceforth “Denu”) as applied to claim 22 above and in further view of Baddoo et al. (J Cell Biochem. 2003 Aug 15;89(6):1235-49.; henceforth “Baddoo”) and Redondo-Castro et al. (Stem Cell Res Ther. 2017 Apr 17;8(1):79.; henceforth “Redondo-Castro”).
The teachings of Pittenger and Denu above are hereby incorporated in their entirety.
Regarding claim 25, further to the discussion of claims 21-22 above, Pittenger and Denu are silent to steps of (a) culturing the cells in an undifferentiated state and (b), culturing the cells from step (a) in the presence of bFGF.
Nevertheless, regarding claim 25, Baddoo teaches a method of preparing bone marrow MSCs comprising the steps of (a) culturing the cells in an undifferentiated state for 3 days (“cultured at 378C with 5% CO2 in a humidified chamber for 72 h” Materials and Methods pg. 1236 col. 2) and (b) culturing the cells of step (a) in the presence bFGF (cultured 7 days in media with FGF2; pg. 1237 col. 1 1st para.). Baddoo teaches FGF2 stimulates growth of MSCs (pg. 1246 col. 1) and inhibits differentiation (pg. 1246 col. 2).
Therefore, regarding claim 25, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention and combine the known prior art elements of (a) culturing the cells in an undifferentiated state for 3 days and (b) culturing the cells of step (a) in the presence bFGF of Baddoo to obtain the predictable result of preparing the foreskin-derived fibroblasts, which are morphologically indistinguishable from and are therefore an obvious variant of bone marrow MSCs as discussed above, for culture in the method of Pittenger. One of ordinary skill would have been motivated to do so as taught by Baddoo to prepare the cells for use after collection in step (a) and to stimulate growth and proliferation of the cells while inhibiting differentiation into an undesired cell type (pg. 1246). Regarding the reasonable expectation of success, Baddoo evidences a method of preparing bone marrow MSCs, comprising the steps of (a) culturing the cells in an undifferentiated state for 3 days (“cultured at 378C with 5% CO2 in a humidified chamber for 72 h” Materials and Methods pg. 1236 col. 2) and (b) culturing the cells of step (a) in the presence bFGF (cultured 7 days in media with FGF2; pg. 1237 col. 1 1st para.). Because, as discussed above, foreskin-derived fibroblasts are morphologically indistinguishable and are therefore an obvious variant, one of ordinary skill would expect them to behave similarly to the MSCs evidenced by Baddoo.
However, regarding claims 25-29, Pittenger , Denu, and Baddoo are silent to the step of activating the cell (instant claim 25), by exposing the cell to IL-1 cytokine in cell culture media (instant claims 26-29).
Nevertheless, regarding claims 25-29, Redondo-Castro teaches method steps of culturing bone Marrow MSCs including activating (priming) the cell (instant claim 25), by exposing the cell to IL-1 cytokine in cell culture media (instant claims 26-29) at a concentration of 1, 10, 50 or 100 ng/mL (instant claims 28-29) (Cell Treatments “MSC Priming” pg. 3 col. 1). Redondo-Castro teaches treatment of MSCs with IL-1α or IL-1β increased the secretion of trophic factors such as G-CSF (pg. 8 col. 1 Discussion). Redondo-Castro teaches that preconditioning treatments with IL-1 increased MSC secretion of anti-inflammatory mediators and trophic factors (pg. 9 col. 2 conclusions). Redondo-Castro teaches IL-1 primes human mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype in vitro (title).
Therefore, regarding claims 25-29, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to practice the method as suggested by Pittenger in view of Baddoo above, and combine the known prior art element of activating (priming) the cell (instant claim 25), by exposing the cell to IL-1 cytokine in cell culture media (instant claims 26-29) at a concentration of 1, 10, 50 or 100 ng/mL (instant claims 28-29) of Redondo-Castro to obtain the predictable result of a primed cell for use in the method. One of ordinary skill would have been motivated to do so as taught by Redondo-Castro to increase the secretion of anti-inflammatory mediators and trophic factors by the cell and to prime the mesenchymal stem cells towards an anti-inflammatory and pro-trophic phenotype (pg. 9 col. 2 conclusions; Title). Regarding the reasonable expectation of success, Redondo-Castro evidences method steps of exposing MSCs to IL-1 cytokine in cell culture media at a concentration of 1, 10, 50 or 100 ng/mL (Cell Treatments “MSC Priming” pg. 3 col. 1). Because, as discussed above, foreskin-derived fibroblasts are morphologically indistinguishable and are therefore an obvious variant, one of ordinary skill would expect them to behave similarly to the MSCs evidenced by Redondo-Castro.
Regarding claims 32-33, further to the discussion of claims 21-22 and 26 above, it is noted that the wherein clauses does not recite any additional active method steps, but simply state a characterization or conclusion of the results of process step positively recited ( “induces an increase in the expression of one or more complement inhibitory molecules” instant claim 32 and “the complement inhibitory molecules are selected from the group consisting of CD35, CD46, C4BP, CD55, Factor H, and a combination thereof”) . Therefore, the "wherein" clauses are not considered to further limit the method defined by the claim and has not been given weight in construing the claims. See Texas Instruments, Inc. v. International Trade Comm., 988 F.2d 1165, 1171,26 USPQ2d 1018, 1023 (Fed Cir. 1993) ("A 'whereby' clause that merely states the result of the limitations in the claim adds nothing to the patentability or substance of the claim."). See also Minton v. National Assoc. of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003) ("A whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited."). See also MPEP 2111.04 that a “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure” and a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Additionally, regarding claims 32-33, as stated above, Pittenger in view of Denu, Baddoo and Redondo-Castro suggest all the active method steps of the instantly claimed method and therefore the claimed results of “an increase in the expression of one or more complement inhibitory molecules” (instant claim 32) where “the complement inhibitory molecules are selected from the group consisting of CD35, CD46, C4BP, CD55, Factor H, and a combination thereof” (instant claim 33), would naturally follow the recitation of the suggested active method steps.
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632 /VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632