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 .
Claims 1, 4, 6-9, 19 and 21-24 are pending in this application and were examined on their merits.
Claim Objections/Rejections withdrawn
The rejection of Claim 8 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to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, has been withdrawn due to the Applicant’s amendments to the claims filed 08/06/2026.
The rejection of Claim(s) 1 and 4 under 35 U.S.C. § 102(a)(1) as being anticipated by Zeng et al. (2018), cited in the IDS, has been withdrawn due to the Applicant’s amendments to the claims filed 08/06/2026.
The rejection of Claim(s) 1, 4 and 6 under 35 U.S.C. § 102(a)(1) as being anticipated by Turner et al. (2017), cited in the IDS, has been withdrawn due to the Applicant’s amendments to the claims filed 08/06/2026.
The rejection of Claim(s) 1, 4, 5, 6, 7, 20, 21 and 22 under 35 U.S.C. § 102(a)(1) as being anticipated by Kang et al. (08/24/2021), cited in the IDS, has been withdrawn due to the Applicant’s submission of a translation of the certified copy of the foreign priority application.
The rejection of Claim(s) 1, 4, 5 and 6 under 35 U.S.C. § 102(a)(1) as being
anticipated by Mehta et al. (2019), as evidenced by Bourin et al. (2014), has been withdrawn due to the Applicant’s amendments to the claims filed 08/06/2026.
The rejection of Claim(s) 1, 4, 5, 6 and 19 under 35 U.S.C. § 103 as being
unpatentable over Mehta et al. (2019), as evidenced by Bourin et al. (2014), and further in view of Zeng et al. (2018), cited in the IDS, has been withdrawn due to the Applicant’s amendments to the claims filed 08/06/2026.
The rejection of Claim(s) 1, 2, 3, 4, 5, 6, 7, 8, 9, 20, 21 and 22 under 35 U.S.C. § 103 as being unpatentable over Mehta et al. (2019), as evidenced by Bourin et al. (2014), in view of Lemenager et al. (2020), cited in the IDS, Louis et al. (2019), cited in the IDS and Yoo et al. (2012), and further in view of Ichida et al. (US 2012/0021519 A1), has been withdrawn due to the Applicant’s amendments to the claims filed 08/06/2026.
Response to Amendment
The Declaration under 37 CFR 1.132 filed 08/06/2026 is insufficient to overcome the rejection of claims 1, 4, 6-9, 19 and 21-24 based upon 35 U.S.C. § 103 as set forth below because:
The Declarant argues that Lemenager utilizes a culture-media containing serum containing endogenous TGFβ, a known inhibitor of angiogenesis and adipocyte hypertrophy. Declarant notes the reference teaches the use of TGFβ/ALK5 inhibitors to counteract this effect. Declarant notes that the instant claims are drawn to a serum-free medium and thus there would be no motivation to use the TGFβ/ALK5 inhibitors. Declarant also assert improper hindsight in combining Mehta and Lemenager as suggested by the Examiner (Declaration, Pg. 2, #s 1-6).
In response to Declarant's argument that the Examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
In this instance, Mehta teaches incubating isolated bovine adipose stromal vascular cells/adipogenic precursors in the stromal vascular fraction. Lemenager teaches that TGFβ is an inhibitor of adipogenesis in adipose stromal cells and that the effects of TGFβ can be overcome by use of TGFβ inhibitors or through the use of serum-free media. Ramakrishnan teaches that the stomal vascular fraction is known to comprise mesenchymal stem cells (MSC), thus the vascular stromal fraction of Mehta would also be expected to comprise MSC. Eggenhofer et al. teaches that MSC constitutively secrete TGF-β. Thus, those of ordinary skill in the art would expect that even if serum-free medium was used, the vascular stromal fraction of Mehta would still contain MSC secreted inhibitory TGFβ which would need to be chemically inhibited.
The Declarant argues that there is no reasonable expectation of success in applying the teachings of references using human cells (Lemenager, Louis) to the bovine cells of Mehta because of a “species barrier”. Declarant notes that Louis indicates adipocyte metabolic pathways and signaling cascades differ between species. Declarant cites Kang as evidence that conventional human adipogenic compositions effective in human and rodent ASC do not induce lipogenesis in bovine ASC. Declarant concludes that the ordinary artisan would therefore not have expected a TGFβ inhibitor effective in human cells would promote adipocyte differentiation in bovine cells (Declaration, Pgs. 2-3, #s1-6).
This is not found to be persuasive for the following reasons, the evidence presented merely indicates that certain combinations of conventional prior art adipogenic compounds are not as effective on bovine ASC as some other species. It is not unexpected that some inter-species variability exists. However, the ordinary artisan would expect that a TGFβ inhibitor effective in inhibiting the effects of TGFβ in a medium for human cells would be just as effective in a medium for bovine cells. Thus, it would be wholly expected that a vascular stromal fraction containing endogenous MSC in serum-free medium, in which said MSC are secreting TGFβ, would have the effects of that TGFβ being inhibited by the presence of a TGFβ inhibitor, thereby increasing adipogenesis.
The Declarant argues that in the claimed method, the ALK5 inhibitor does not have a standard linear dose-response but exhibits an unexpected step-like response that reaches a plateau within the claimed range. Declarant cites Fig. 4 of the Specification wherein lipid production in bovine ASC is low and insufficient at 1 µM, at 5 µM adipogenesis increases 3x over control and at 10µm adipogenesis remains steady. Declarant asserts that the plateau indicates that maximum inhibition is reached at 5 µM and this effect could not have been reasonably predicted. Declarant argues that the ordinary artisan would have expected a linear increase or that the inhibitor remain ineffective (Declaration, Pg. 4, #s 1-3).
This is not found to be persuasive for the following reasons, Declarant has provided only 3 data points (two end, one middle) which is insufficient to demonstrate the criticality of the entirety of the claimed range. See the MPEP at 716.02(d), II. Declarant opines that the abrupt jump in adipogenesis seen in moving from 1µM to 5 µM is “unexpected” but does not provide any data at 2, 3, 4, 6, 7, 8 or 9 µm inhibitor. Further, it is known that there is a saturation point at which no more effect is seen in a treatment (plateau) no matter how much extra treatment is added. This is also not unexpected.
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.
Claim 24 is newly 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 24 recites, “wherein the three-dimensional tissue construct has a remaining rate of 70% or more after trypsin treatment with a trypsin concentration of 0.25% at a temperature of 37°C and a pH 7.4 for a reaction time of 15 minutes”.
It is unclear if the limitation is directed to a property/characteristic of the three dimensional tissue construct or requires an active step of trypsin treatment. For purposes of examination, the limitation has been construed as describing an inherent property of the claimed 3D tissue construct.
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.
Claim(s) 1, 4, 6 and 19 are newly rejected under 35 U.S.C. § 103 as being
unpatentable over Mehta et al. (2019), of record, in view Zeng et al. (2018), Lemenager et al. (2020), both cited in the IDS, Colombier et al. (2014), Ramakrishnan et al. (2018) and Eggenhofer et al. (2014), as necessitated by Applicant’s amendments to the claims filed 08/06/2026.
Mehta et al. teaches incubating isolated (therefore not comprising any mature
adipocytes which are in the aqueous supernatant, see Pg. 117, Fig. 1) bovine adipose
stromal vascular cells/adipogenic precursors in the stromal vascular fraction for 1-2 weeks (or 168-336 hours) (Pg. 116-117, Methods, 3.1 and Fig. 1) in the presence of: erucic acid, elaidic acid, oleic acid, palmitoleic acid, myristoleic acid, phytanic acid and pristanic acid to induce adipogenesis (Pg. 112, Table and Pg. 119, Paragraph 3.2), and reading on Claims 1, 4 and 6.
The reference further teaches culturing bovine adipose cells in alginate scaffolds for 3D tissue culture (Pgs. 120-122, Paragraph 3.3).
The teachings of Mehta et al. were discussed above.
Mehta et al. did not teach a method wherein the medium is a serum-free culture medium, and the content of the fatty acids in the culture medium is 50-150 µM, as now required by Claim 1,
wherein the content of each of the fatty acids in the culture medium is 80-120 µM, as required by Claim 19;
or wherein the cells are incubated in the presence of a TGFß type I receptor inhibitor, wherein the TGFß type I receptor inhibitor is an ALK5 inhibitor at a concentration of 5-10 µM, as now required by Claim 1.
Zeng et al. teaches a method comprising incubating isolated human adipose
derived stem cells (hADSC) in the presence of; 50, 80 or 100 µM oleic acid to induce
adipogenesis of the hADSC (Pgs. 2-3, Paragraph "Culture and Differentiation" and Pg.
3, Column 2, 2ⁿᵈ paragraph).
Lemenager et al. teaches culturing human adipose stem cells (hASC) in a serum-media in the presence of 1 µM of the TGFß type I receptor inhibitors, SB431542 or SB505124 ALK5 (Pgs. 783-784, Paragraph 2.1) wherein TGFß type I receptor inhibition increased the cells adipogenic potential by inhibiting the effects of endogenous TGFβ in the culture media by culturing in serum-free EGM2 media (Pg. 782, Abstract).
Colombier et al. teaches the use of the TGFß type I receptor inhibitor SB505124 with hASC cells at 5 µm (Pg. 5428, Column 2, Methods).
Ramakrishnan et al. teaches that the stomal vascular fraction is known to comprise mesenchymal stem cells (MSC) (Pg. 290, Table 1).
Eggenhofer et al. teaches that MSC constitutively secrete TGF-β (Pg. 5, Column 1, Lines 14-15).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the instant invention to modify the method of Mehta et al. of incubating isolated bovine adipose stromal vascular cells/adipogenic precursors in the presence of a medium comprising fatty acids to use a serum-free medium as taught by Lemenager et al. because TGFβ found in serum culture inhibits adipogenesis of the ASC. Those of ordinary skill in the art would have been motivated to make this modification because serum media is known to contain endogenous TGFβ. There would have been a reasonable expectation of success in making this modification because Mehta teaches inhibiting the effects of TGFβ by either chemical inhibition or through use of serum-free medium.
While the Mehta reference does not specifically teach the limitation of the concentration of all of the fatty acids in the composition being 80-120 µM, one of
ordinary skill in the art would recognize that the concentration of each of the fatty acids
in an adipogenic composition is a result-effective optimizable variable. Zeng et al.
teaches that the fatty acid oleic acid can induce adipogenesis in adipose derived stem
cells at concentrations of 50, 80 or 100 µM (both of which are within the claimed concentration range). This is motivation for someone of ordinary skill in the art to practice or test all of the fatty acid concentration parameter values widely to find those that are functional or optimal for induction of adipogenesis, which would be inclusive or cover the values as instantly claimed.
Absent any teaching of criticality by the Applicant concerning the fatty acid concentration in the composition, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are an optimizable variable which can be met as a matter of routine optimization (see MPEP § 2144.05 (II)(B).
It would have been obvious to those of ordinary skill in the art before the effective
filing date of the claimed invention to modify the method of Mehta et al. and Zeng et al. of incubating adipose stem cells in a serum-free media with free fatty acids to induce adipogenesis to further include 5 µM of the TGFß type I receptor inhibitor SB505124 ALK5 as taught by Lemenager et al. and Colombier et al. because Ramakrishnan et al. teaches the stromal vascular fraction of Mehta et al. contains MSC and Eggenhofer et al. teaches that MSC constitutively express TGFβ, which will inhibit the angiogenic potential of the ASC cells of Mehta. Lemenager et al. teaches the use of TGFβ inhibitors (including SB505124 ALK5) to counteract the effect of TGFβ in the culture media and Colombier et al. teaches that 5µM is a suitable concentration of SB505124 which can be used on hASC. Those of ordinary skill would have been motivated to make this modification in order to eliminate the effects of TGFβ produced by MSC in the stromal vascular fraction and produce more adipocytes from the adipose stem cells in the composition. There would have been a reasonable expectation of success in making this modification because at least the Mehta and Lemenager methods are reasonably drawn to the same field of endeavor, that is, the induction of adipogenesis of adipose-derived stem cells.
With regard to Claim 24, as the cited prior art makes obvious the limitations of Claim 1, the inherent properties and characteristics thereof would also be found in the prior art 3D tissue construct.
Claim(s) 1, 4, 6, 7, 8, 9 and 19 are rejected under 35 U.S.C. § 103 as being
unpatentable over Mehta et al. (2019), of record, in view of Zeng et al. (2018), Lemenager et al. (2020), both cited in the IDS, Ramakrishnan et al. (2018), Eggenhofer et al. (2014) and Colombier et al. (2014), as applied to Claims 1, 4, 6 and 19 above, and further in view of Louis et al. (2019), cited in the IDS.
The teachings of Mehta et al., Zeng et al., Lemenager et al., Ramakrishnan et al. (2018), Eggenhofer et al. (2014) and Colombier et al. were discussed above.
None of the above references taught a method wherein the cells are incubated with a TGFß type I receptor inhibitor and fragmented collagen disposed between the cells in a 3D construct, as required by Claims 7-9.
Louis et al. teaches incubating adipose derived stem cells with homogenized
(defibered) fragmented collagen (microfibers) (Pgs. 195-196, Paragraph 2.1) disposed
between the cells in a 3D construct (Pg. 196, Fig. 1B) wherein the construct increased
adipogenic gene expression and produced larger fat vesicles as well as increased
markers of functionality (Pg. 194, Abstract).
It would have been obvious to those of ordinary skill in the art before the effective
filing date of the claimed invention to modify the method of Mehta et al., Zeng et al., Lemenager et al., Ramakrishnan et al., Eggenhofer et al. and Colombier et al. of incubating cells comprising adipose stem cells with free fatty acids and TGFß type I receptor inhibitor SB505124 ALK5 to induce optimal adipogenesis to include fragmented collagen microfibers disposed between the cells in a 3D construct as taught by Louis et al. because this would further increase the adipogenic potential of the stem cells in the composition. Those of ordinary skill would have been motivated to make this modification in order to produce more adipocytes from the adipose stem cells in the composition. There would have been a reasonable expectation of success in making this modification because at least the Mehta, Lemenager and Louis references are reasonably drawn to the same field of endeavor, that is, the induction of adipogenesis of adipose-derived stem cells.
Claim(s) 1, 4, 6, 19 and 21 are rejected under 35 U.S.C. § 103 as being
unpatentable over Mehta et al. (2019), of record, in view of Zeng et al. (2018), Lemenager et al. (2020), both cited in the IDS, Ramakrishnan et al. (2018), Eggenhofer et al. (2014) and Colombier et al. (2014), as applied to Claims 1, 4, 6 and 19 above, and further in view of Louis et al. (2019), cited in the IDS, and Yoo et al. (2012), of record.
The teachings of Mehta et al., Zeng et al., Lemenager et al., Ramakrishnan et al. (2018), Eggenhofer et al. and Colombier et al. were discussed above.
None of the above references taught a method wherein the adipose stem cells are incubated in a fatty acid culture medium comprising a defibered collagen component, fibrinogen and thrombin, as required by Claim 21.
Louis et al. teaches incubating adipose derived stem cells with homogenized (defibered) fragmented collagen (microfibers) (Pgs. 195-196, Paragraph 2.1) disposed between the cells in a 3D construct (Pg. 196, Fig. 1B) wherein the construct increased adipogenic gene expression and produced larger fat vesicles as well as increased markers of functionality (Pg. 194, Abstract).
Yoo et al. teaches the transplantation of adipose stem cells (ASC) to an ischemic bowel wall in a mixture of thrombin and fibrinogen for stable fixation to the bowel wall (Pg. 134, Columns 1-2, "Local Implantation" and Fig. 1).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Mehta et al., Zeng et al., Lemenager et al., Ramakrishnan et al., Eggenhofer et al. and Colombier et al. of incubating cells comprising adipose stem cells with free fatty acids and the TGFß type I receptor inhibitor SB505124 ALK5 to induce optimal adipogenesis to include fragmented collagen microfibers disposed between the cells in a 3D construct as taught by Louis et al. and include thrombin and fibrinogen as taught by Yoo et al. because this would further increase the adipogenic potential of the stem cells in the composition as well as provide a stable matrix for transplantation in vivo.
Those of ordinary skill would have been motivated to make this modification in order to produce more adipocytes from the adipose stem cells in the composition and stably transplant those cells to a subject. There would have been a reasonable expectation of success in making this modification because all three references are reasonably drawn to the same field of endeavor, that is, the induction of adipogenesis of adipose-derived stem cells or the use thereof.
Claim(s) 1, 4, 6, 19, 21 and 22 are newly rejected under 35 U.S.C. § 103 as being unpatentable over Mehta et al. (2019), of record, in view of Zeng et al. (2018), Lemenager et al. (2020), both cited in the IDS, Ramakrishnan et al. (2018), Eggenhofer et al. (2014), Colombier et al. (2014), Louis et al. (2019), cited in the IDS, and Yoo et al. (2012), of record, as applied to Claims 1, 4, 6, 19 and 21 above, and further in view of Keller et al. (US 2019/0111086 A1), as necessitated by Applicant’s amendments to the claims filed 08/06/2026.
The teachings of Mehta et al., Zeng et al., Lemenager et al., Ramakrishnan et al., Eggenhofer et al., Colombier et al., Louis et al. and Yoo et al. were discussed above. The Examiner notes that Lemenager et al. teaches culturing human adipose stem cells (hASC) in the presence of 1 µM of the TGFß type I receptor inhibitors; SB431542 or the ALK5 inhibitor SB505124 (Pgs. 783-784, Paragraph 2.1)
None of the above references taught a method wherein the culture medium
comprises the TGFß type I receptor inhibitor E-616452, as required by Claim 22.
Keller et al. teaches the TGFß type I receptor inhibitors include RepSox/E-616452, SB505124 and SB431542 (both taught by Lemenager et al.) (Pg. 9, Paragraph [0143]).
It would have been obvious to those of ordinary skill in the art before the effective
filing date of the claimed invention to modify the method of Mehta et al., Zeng et al., Lemenager et al., Ramakrishnan et al., Eggenhofer et al., Colombier et al., Louis et al. and Yoo et al. of incubating cells comprising adipose stem cells with free fatty acids and TGFß type I receptor inhibitor SB431542 or SB505124 ALK5 inhibitor, thrombin, fibrinogen and fragmented collagen microfibers disposed between the cells in a 3D construct to substitute the E-616452 TGFß type I receptor inhibitor of Keller et al. for the SB431542 or SB505124 ALK5 TGFß type I receptor inhibitor of Lemenager et al. because it is prima facie obvious to substitute art-recognized equivalents for the same purpose. See the MPEP at 2144.06, II. Those of ordinary skill would have been motivated to make this modification in order to reduce TGFß inhibition of adipogenesis to produce more adipocytes from the adipose stem cells in the composition. There would have been a reasonable expectation of success in making this modification because the art recognizes SB431542, SB505124 and E616452 as equivalent inhibitors of TGFß type I receptor.
Claim(s) 1, 4, 6, 19 and 23 are newly rejected under 35 U.S.C. § 103 as being
unpatentable over Mehta et al. (2019), of record, in view of Zeng et al. (2018), Lemenager et al. (2020), both cited in the IDS, Ramakrishnan et al. (2018), Eggenhofer et al. (2014) and Colombier et al. (2014), and further in view of Zakhari et al. (2018) and Si et al. (WO 2018/106652 A1).
The teachings of Mehta et al., Zeng et al., Lemenager et al., Ramakrishnan et al., Eggenhofer et al. and Colombier et al. were discussed above.
None of the above references taught a method wherein the three-dimensional tissue construct includes and intercellular vascular network, as now required by Claim 23.
Zakhari et al. teaches that the adipose stromal vascular fraction (SVF) is a heterologous cell source that contains endothelial cells, pericytes, smooth muscle cells, stem cells and other accessory immune or stromal cells and SVF cell populations have vasculogenic and angiogenic potential and demonstrate cell aggregation and clustering on ECM within 36 hours of seeding (Pg. 32, Abstract).
Si et al. teaches a method for producing an engineered vasculature comprising forming an organoid comprising endothelial cells and mesenchymal stem cells embedded in a hydrogel (Pg. 61, Claim 1), wherein the MSC are derived from adipose tissue (Pg. 61, Claim 6).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Mehta et al., Zeng et al., Ramakrishnan et al., Eggenhofer et al. and Colombier et al. of incubating adipose stem cells with free fatty acids to induce adipogenesis that the tissue construct will comprise an intercellular vascular network because Mehta teaches the use of a stomal vascular fraction comprising bovine adipose stromal vascular cells/adipogenic precursors and Zakhari teaches that the adipose stromal vascular fraction contains endothelial cells, pericytes, smooth muscle cells, stem cells and other accessory immune or stromal cells has vasculogenic potential and Si teaches that in vitro vasculature forming an organoid comprising endothelial cells and mesenchymal stem cells embedded in a hydrogel. Thus, the ordinary artisan would have recognized that the stromal vascular fraction of Mehta when cultured would produce an intercellular vascular network by vasculogenesis, particularly as it contains all the cell types necessary for doing so. Those of ordinary skill in the art would have been motivated to make this modification in order to prepare a tissue culture in vitro which mimics tissue in vivo. There would have been a reasonable expectation of success in making this modification because Mehta provides the necessary cells types and conditions for the formation of an intercellular vascular network in vitro.
Response to Arguments
Applicant’s arguments, see Remarks, filed 08/06/2026, with respect to the above withdrawn rejections have been fully considered and are persuasive.
The remaining arguments have been considered only insofar as they apply to the new rejections herein.
The Applicant argues that Lemenager utilizes a culture-media containing serum containing endogenous TGFβ, a known inhibitor of angiogenesis and adipocyte hypertrophy. Applicant notes the reference teaches the use of TGFβ/ALK5 inhibitors to counteract this effect. Applicant further notes that the instant claims are drawn to a serum-free medium and thus there would be no motivation to use the TGFβ/ALK5 inhibitors (Remarks, Pg. 8, Lines 7-21).
This is not found to be persuasive for the following reasons, Mehta teaches incubating isolated bovine adipose stromal vascular cells/adipogenic precursors in the stromal vascular fraction. Lemenager teaches that TGFβ is an inhibitor of adipogenesis in adipose stromal cells and that the effects of TGFβ can be overcome by use of TGFβ inhibitors or through the use of serum-free media. Ramakrishnan teaches that the stomal vascular fraction is known to comprise mesenchymal stem cells (MSC), thus the vascular stromal fraction of Mehta would also be expected to comprise MSC. Eggenhofer et al. teaches that MSC constitutively secrete TGF-β. Thus, those of ordinary skill in the art would expect that even if serum-free medium was used, the vascular stromal fraction of Mehta would still contain MSC-secreted inhibitory TGFβ which would need to be chemically inhibited.
The Applicant argues that there is no reasonable expectation of success in applying the teachings of references using human cells (Lemenager, Louis) to the bovine cells of Mehta because of a “species barrier”. Applicant notes that Louis indicates adipocyte metabolic pathways and signaling cascades differ between species. Applicant cites Kang as evidence that conventional human adipogenic compositions effective in human and rodent ASC do not induce lipogenesis in bovine ASC. Applicant concludes that the ordinary artisan would therefore not have expected a TGFβ inhibitor effective in human cells would promote adipocyte differentiation in bovine cells (Remarks, Pg. 8, Lines 22-25 and Pg. 9 and Pg. 10, Lines 1-4).
This is not found to be persuasive for the following reasons, the evidence presented merely indicates that certain combinations of conventional prior art adipogenic compounds are not as effective on bovine ASC as some other species. It is not unexpected that some inter-species variability exists. However, the ordinary artisan would expect that a TGFβ inhibitor effective in inhibiting the effects of TGFβ in a medium for human cells would be just as effective in a medium for bovine cells. Thus, it would be wholly expected that a vascular stromal fraction containing endogenous MSC in serum-free medium, in which said MSC are secreting TGFβ, would have the effects of that TGFβ being inhibited by the presence of a TGFβ inhibitor, thereby increasing adipogenesis.
The Applicant argues that in the claimed method, the ALK5 inhibitor does not have a standard linear dose-response but exhibits an unexpected step-like response that reaches a plateau within the claimed range. Applicant cites Fig. 4 of the Specification wherein lipid production in bovine ASC is low and insufficient at 1 µM, at 5 µM adipogenesis increases 3x over control and at 10µm adipogenesis remains steady. Applicant asserts that the plateau indicates that maximum inhibition is reached at 5 µM and this effect could not have been reasonably predicted. Applicant argues that the ordinary artisan would have expected a linear increase or that the inhibitor remain ineffective (Remarks, Pg. 10, Lines 5-24 and Pg. 11, Lines 1-8).
This is not found to be persuasive for the following reasons, Applicant has provided only 3 data points (two end, one middle) which is insufficient to demonstrate the criticality of the entirety of the claimed range. See the MPEP at 716.02(d), II. Applicant opines that the abrupt jump in adipogenesis seen in moving from 1µM to 5 µM is “unexpected” but does not provide any data at 2, 3, 4, 6, 7, 8 or 9 µm inhibitor. For all the Examiner knows, the missing data provides evidence of an entirely predictable linear dose response. Further, it is known in the art that there is a saturation point at which no more effect is seen in a treatment no matter how much extra treatment is added. This is exemplified by a plateau in a dose response curve and is also not unexpected.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, Applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/PAUL C MARTIN/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653
Prosecution Insights