Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
DETAILED OFFICE ACTION
This Office Action is in response to the papers filed 19 August 2025.
CLAIMS UNDER EXAMINATION
Claims 1-2, 4, 6-7, 11-12, 23, 29 and 31-33 have been examined on their merits.
PRIORITY
Provisional Application 61/339526, filed on 05 March 2010, is acknowledged.
REJECTIONS
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 23, 29 and 31-33 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Silva (previously cited; Spatiotemporal control of vascular endothelial growth factor delivery from injectable hydrogels enhances angiogenesis. Journal of Thrombosis and Haemostasis, 2007 5: 590–598) in view of Ylikomo et al. (Methods and means for soft tissue engineering. US20110151005 with benefit of WO2010/026299 filed 07 September 2009).
Silva teaches an injectable alginate gel comprising recombinant human VEGF165 (page 591, right column, second paragraph). The alginate gel is formed as follows:
Ultrapure alginates were purchased from ProNova Biomedical (Norway). MVG alginate, a high-G-containing alginate (M/G ratio of 40/60 as specified by the manufacturer) was used as the high molecular weight (molecular mass ¼ 250 000 Da) component to prepare gels. LMW alginate (molecular mass ¼ 50 000 Da) was obtained by c-irradiating high molecular weight alginate with a cobalt-60 source for 4 h at a c-dose of 5.0 Mrad (Phoenix Lab, University of Michigan, Ann Arbor, MI,USA), as specified by Kong et al. [24]. The alginate used to form gels was a combination of the two different molecular weight polymers at a ratio of 7.5:2.5. Both alginate polymers were diluted to 1%w/v in double-distilled H2O, and 1% of the sugar residues in the polymer chains were oxidized with sodium periodate (Aldrich, St Louis, MO, USA) by maintaining solutions in the dark for 17 h at room temperature, as previously described [21]. An equimolar amount of ethylene glycol (Fisher, Pittsburgh, PA, USA) was added to stop the reaction, and the solution was subsequently dialyzed (MWCO 1000, Spectra/Por_) over 3 days. The solution was sterile filtered, frozen (-20 °C overnight), lyophilized and stored at -20 °C. To prepare gels, modified alginates were reconstituted in EBM-2 (Cambrex Corporation, Walkersville,MD, USA) to obtain a 2%w/v solution (75%LMW, 25%MVG used in all experiments) prior to gelation. The 2% w/v alginate solutions were cross-linked with aqueous slurries of a calcium sulfate solution (0.21 g CaSO4 mL)1 distilled H2O) at a ratio of 25:1 (40 lL of CaSO4 per 1 mL of 2% w/v alginate solution) using a 1-mL syringe. Reconstituted alginate was stored at 4 °C.
Therefore Silva teaches alginate gels comprising a combination of low (50,000 Da) and high (250,000 Da) molecular weight oxidized alginates.
Silva teaches the gel is used to treat ischemia muscle (Summary; see page 597, left column, second paragraph). Silva teaches VEGF alone may not be sufficient, and discloses future studies may involve combining VEGF delivery with other angiogenic factors to augment and mature the angiogenic response (page 598, left column, first paragraph). Silva teaches the disclosed system may also be broadly useful for the manipulation or exploitation of the presentation of a wide variety of other growth factors (see last paragraph of page 598).
The deficiency of Silva is that it does not teach incorporation of IGF-1.
Ylikomo teaches a composition comprising a predetermined amount of VEGF, FGF-2, IGF-1 and a biocompatible matrix ([0009]). The matrix can be a hydrogel ([0025]). The hydrogel can be alginate ([0025] [0050]). The implant can be injectable ([0025]).
The concentration of VEGF may vary between about 1 pg/ml and about 1400 pg/ml ([0037]). The concentration of IGF-1 may vary between about 100 pg/ml to about 1500 pg/ml ([0037]). Example 5 discloses 200 pg/ml IGF-1 and 65 pg/ml VEGF ([0103]).
The implant can be used in soft tissue repair or engineering, angiogenesis induction in tissue engineering and in treating ischemic conditions ([0025]). The art teaches muscle is a soft tissue ([0003]).
It would have been obvious to combine the teachings of the prior art by using IGF-1 in the hydrogel taught by Silva. One would have been motivated to do so since Silva teaches a hydrogel implant for treating ischemic soft tissue comprising VEGF165 and Ylikomo teaches IGF-1 can be used with VEGF to treat an ischemic soft tissue. One would have had a reasonable expectation of success since Silva teaches the disclosed hydrogel can be used with additional growth factors. One would have expected similar results since both references teach use alginate hydrogels to treat ischemic tissue. While Ylikomo does not explicitly teach a 1:1 ratio, the art teaches ranges of VEGF and IGF-1 that would encompass the claimed ranges. Further, MPEP 2133.03 discloses the following:
“In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).”
Therefore, the examiner asserts the claimed concentration is prima facie obvious.
Therefore claim 1 is rendered obvious.
Silva teaches the alginate used to form gels is a combination of the two different molecular weight polymers at a ratio of 7.5:2.5 (supra). Neither the claims nor the instant specification disclose the values encompassed by the term “about”. Therefore the ratio taught by Silva is interpreted be about 1:1. Therefore claim 23 is rejected.
The gel taught by Silva comprises oxidized low and oxidized high molecular weight alginate (supra). Therefore claim 29 is rejected.
Silva teaches the alginate comprises 1% oxidized alginate (supra). Therefore claim 31 is included in this rejection.
Silva teaches MVG alginate, a high-G-containing alginate (M/G ratio of 40/60 as specified by the manufacturer) was used as the high molecular weight (molecular mass ¼ 250 000 Da) component to prepare gels (supra). Therefore claims 32 and 33 are included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
Claims 2, 4, 6-7 and 11-12 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Silva in view of Ylikomo as applied to claim 1 above, and further in view of Mooney et al. (Polymers Containing Polysaccharides Such As Alginates Or Modified Alginates. Patent 6642363B1 2003).
Claim 1 is rejected on the grounds stated above. The teachings of the prior art are reiterated. Silva teaches an alginate gel comprising growth factors.
Silva does not teach a population of myogenic cells (claim 2).
The art is silent regarding the presence of macropores (claim 4).
The art does not teach the hydrogel is in lyophilized and compressed state (claim 6).
The art does not teach the hydrogel has shape-memory (claim 7).
The art is silent regarding the presence of open, interconnected pores (claim 11).
The art is silent regarding macropores of 5-500 microns in diameter (claim 12).
Mooney et al. disclose a crosslinked alginate, and teach it may be formulated to deliver growth factors (Abstract; column 17, lines 19-21, 64-65). Example 3 discloses the adhesion of skeletal myoblasts on the matrices (see column 25). In Study 4, Mooney prepares a crosslinked alginate comprising “large pores”. A large pore is broadly interpreted to be a macropore. Mooney teaches “open structures with large pore sized, e.g., (d>10 μm) are typically utilized if the new tissue is expected to integrate with the host tissue” (column 21, lines 47-50). The large pores illustrated in Figure 5 of Mooney are interpreted to be interconnected.
Mooney teaches a method of preparation that comprises lyophilizing and compressing crosslinked alginate (See Study 3).The art teaches doing so when preparing matrices with “shape memory”. Shape memory matrices are designed to “remember” their original dimensions and, following injection in the body in a compact (hence, compressed) form, resume their original size and shape. The shape memory property of the alginate is provided by crosslinking thereof (column 10, lines 29-45). The art teaches shape memory allows lyophilized alginate matrices to act as a sponge that can return to its original shape after being compressed and rehydrated (Example 14). Shape memory is advantageous during tissue engineering where size and shape of the matrix is important (line 65 of column 1, through line 2 of column 2).
The art teaches the disclosed composition is advantageously useful as a vehicle for sustained release drug delivery (column 22, lines 39-40).
It would have been obvious to combine the teachings of the prior art by adding myogenic cells to Silva’s hydrogel. One would have been motivated to do since Silva teaches alginate hydrogels can be used for cell immobilization (page 591, left column, first paragraph) and Mooney teaches immobilization of myoblasts (myogenic cells). One would have had a reasonable expectation of success since Mooney teaches myogenic cells can be immobilized on alginate hydrogels. One would have expected similar results since both references are directed to alginate gels for growth factor delivery. Therefore claim 2 is included in this rejection.
It would have been obvious to prepare a gel with macropores. One would have been motivated to do so since Silva teaches an alginate hydrogel to deliver growth factors and Mooney teaches preparing alginate hydrogels with macropores to deliver growth factors. One would have had a reasonable expectation of success since Mooney teaches alginate gels with micropores can successfully deliver growth factors. One would have expected similar results since both references are directed to alginate gels for growth factor delivery. Therefore claim 4 is included in this rejection.
It would have been obvious to lyophilize and compress an alginate, as disclosed by Mooney, when preparing a matrix with shape memory. One would have been motivated to do so since Silva teaches an injectable alginate hydrogel to deliver growth factors and Mooney teaches lyophilizing and compressing alginate gels. Mooney teaches doing so allows the gel to reform its shape upon placement in the body. One would have had a reasonable expectation of success since Mooney teaches alginate gels used to deliver growth factors can be lyophilized and compressed. One would have expected similar results since both references are directed to alginate gels for growth factor delivery. Therefore claim 6 is included in this rejection. Mooney teaches a gel with shape memory (supra). Therefore claim 7 is included in this rejection.
It would have been obvious to combine the teachings of Silva and Mooney by using an alginate with interconnected pores since Mooney teaches alginates with pores may be formulated for delivery of growth factors. One would be motivated to use an alginate with large pores since Silva delivers growth factors to a tissue, and Mooney teaches these gels facilitate integration in host tissue. Consequently, one would use an alginate with pores that integrates and delivers growth factors to a muscle in need of treatment. One would have expected similar results since Silva and Mooney teach alginate gels that deliver growth factors. Therefore claim 11 is included in this rejection.
It would have been obvious to prepare a gel with macropores about 5-500 microns in diameter. One would have been motivated to do so since Silva teaches an alginate hydrogel for implantation and Mooney teaches large pore sizes with diameter greater than 10 microns are typically used if a tissue is expected to integrate in a host. One would have had a reasonable expectation of success since Mooney teaches alginate gels with micropores can successfully be used for implantation. One would have expected similar results since both references are directed to alginate gels for growth factor delivery. Therefore claim 12 is included in this rejection.
Therefore Applicant’s Invention is rendered obvious as claimed.
APPLICANT’S ARGUMENTS
The arguments made in the response filed on 19 August 2025 are acknowledged.
The Applicant argues Silva does not teach incorporation of IGF-1 and Ylikomi does not teach a 1:1 ratio of VEGF and IGF-1. The arguments state Examples 2, 3 and 5 disclose VEGF:IGF in a ratio of 1:39.7, 40.2 and 3.3, respectively. The Applicant argues there is no reason to combine the cited references. The Applicant alleges Ylikomo teaches IGF-1 to promote adipogenesis, and teaches away from combining VEGF and IGF-1 to treat ischemic soft tissue.
EXAMINER’S RESPONSE
The arguments are not persuasive. The teachings of Silva are reiterated. Silva teaches an oxidized alginate hydrogel comprising VEGF165. Silva suggests combination with additional angiogenic factors. The rejection above acknowledges Silva does not teach IGF-1 as an angiogenic factor.
Ylikomi teaches an implant comprising “adipose tissue extract”, VEGF, FGF-2, IGF-1 and a biocompatible matrix ([0009]). “Adipose tissue extract” is a cell-free cytokine mixture of bioactive substances expressed by cells found in fat including adipogenic and angiogenic factors ([0031] [0034]). The art teaches a composition comprising VEGF, FGF-2 and IGF-1 can be used to stimulate angiogenesis, including treating ischemic conditions ([0035]). The art teaches this kind of composition “is particularly useful in stimulating angiogenesis” ([0035]). Ylikomi teaches injection of a composition comprising VEGF, IGF-1 and FGF-2 results in neovascularization and adipose tissue formulation in the implant area ([0105] of Example 5). Therefore the art does not teach away from using VEGF and IGF-1 together.
Ylikomi teaches the composition can be used to repair soft tissue, induce angiogenesis and treat ischemic conditions ([0024][0025]). “Soft tissue” includes muscle, connective tissue, adipose tissue and blood vessels ([0003]). The art teaches formation of blood vessels is crucial for regenerating soft tissue ([0007]). The art teaches the following at [0029]:
The present disclosure is based on studies attempting to provide a microenvironment that is suitable for cell proliferation and differentiation, thus resulting in formation of blood vessels and adipose tissue without exogenous transplantation of cells. An optimal microenvironment enhances migration of adipose stem cells from the surrounding tissue and induces differentiation of endothelial and adipocyte precursor cells into mature adipocytes, loose connective tissue and muscle cells and vascular cells. Neovascularization in the developing tissue is used to avoid necrosis and scar formation.
The skilled artisan would administer a composition comprising VEGF and IGF-1 since Ylikomi teaches the combination of angiogenic factors provides a microenvironment that is suitable for cell proliferation and differentiation, thus resulting in formation of blood vessels and adipose tissue.
The combination of angiogenic factors to treat an ischemic soft tissue is rendered obvious. It is noted that [0035] of Ylikomi teaches a lower concentration of VEGF (e.g., 1pg) is suitable for adipogenesis while an increased concentration of VEGF (at least 7pg) produces an angiogenic effect. Absent evidence of criticality, the skilled artisan would optimize the ratio of VEGF and IGF-1 to obtain the desired effect.
CONCLUSION
No Claims Are Allowed
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 extension fee 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 date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE MOSS whose telephone number is (571) 270-7439. The examiner can normally be reached on Monday-Friday, 8am-5pm EST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sharmila Landau can be reached on (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is (571) 273-8300.
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/NATALIE M MOSS/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653