DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Response to Amendments
Applicant's amendments filed 7/21/25 to claim 37 has been entered. Claims 1-7, 9, 11-16, 29-31 and 35-37 remain pending and are being considered on their merits. References not included with this Office action can be found in a prior action. Any rejections of record not particularly addressed below are withdrawn in light of the claim amendments and applicant’s comments.
Election/Restrictions
Applicant’s election of Group I, and the species of a combination of collagen and fibronectin, and a combination of pressure and temperature, in the reply filed on 1/20/2022 stands.
Applicant should note that the rejections below are identical to those in the Office Action mailed 1/21/2025, with the exception of those addressing the limitations of amended claim 37.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
Claims 1-3, 5, 11-12, 14, 29-30, 35 and 37 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Ozbas et al (U.S. PUB 20070128175).
Regarding claims 1-3, 5, 14 and 35, Ozbas teaches a method comprising suspending and encapsulating mesenchymal stem cells in a hydrogel matrix with a rigidity ranging from 100 Pa to 550 Pa, wherein the gel is exposed to temperature and pressure of the environment which results in an increase rigidity over time (see Example 3 and Figure 30B). Regarding claims 1 and 35, Ozbas teaches that mesenchymal stem cells can be in the hydrogel for at least 48 hours (see Example 2).
Regarding claim 11, Ozbas gel with encapsulated cells reads on being “3-dimensional” (see Figure 29).
Regarding claim 12, Ozbas teaches the that the medium supporting the cells comprises fetal bovine serum (FBS) (see Example 3).
Regarding claims 1, 29 and 35, Ozbas shows that cells in the gel have a rounded morphology after being suspended in the gel (see Figure 29); reads on “after the initial active step of suspending” as the morphology is shown at a time point (i.e., any time point) after the initial active step of suspending begins.
Regarding claims 1, 30 and 35, Ozbas teaches seeding (reads on suspending) quiescent cells (reads on arrested in the cell cycle) in the gel (see paragraph [0144]); therefore, this teaching reads on the cells being in a quiescent state, and arrested in the cell cycle, “after the initial active step of suspending” as the morphology is shown at a time point (i.e., any time point) after the initial active step of suspending begins.
Regarding claim 37, Ozbas teaches calf serum (fetal bovine serum) can then be added 72 hours after suspending cells in the hydrogel matrix, and that said serum effects the growth properties of cells (see Example 3 and paragraphs [0052], [0110] and [0143]-[0144]); reads on “exposing the gel to a growth modulating factor”, “wherein the exposing the gel matrix to a growth modulating factor step is after the suspending step”.
Ozbas does not teach the rigidity of the gel when the cells are in said gel for two days (claims 1 and 35).
It would have been obvious to keep the cells in Ozbas’ hydrogel with a rigidity ranging from 100 Pa to 550 Pa for at least two days to obtain cells with a rounded morphology. A person of ordinary skill in the art would have had a reasonable expectation of success in keeping the cells in Ozbas’ hydrogel with a rigidity ranging from 100 Pa to 550 Pa for at least two days to obtain cells with a rounded morphology because Ozbas teaches that cells can be in the hydrogel for at least two days and the cell in the hydrogel have a rounded morphology. The skilled artisan would have been motivated to keep the cells in Ozbas’ hydrogel with a rigidity ranging from 100 Pa to 550 Pa for at least two days to obtain cells with a rounded morphology because Ozbas teaches keeping the cells in the hydrogel for this length of time, thereby establishing that it is useful, and Ozbas teaches obtaining cells in the hydrogel with a rounded morphology.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claims 1-7, 11-16, 30 and 35-37 remain rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Healy et al (US PGPUB 20070026518) in view of Weissman (US PGPUB 20040171559).
Regarding claims 1 and 35, Healy is drawn to polymer-based hydrogel substrates (reads on “gel matrix”) for modulating stem cell adhesion, stem cell growth, stem cell proliferation, stem cell self-renewal, stem cell differentiation, or combinations thereof (see abstract and paragraphs [0007], [0046] and [0236]). Regarding claims 1 and 35, Healy teaches that mesenchymal stem cells (MSCs) are a useful type of stem cell to be used with the polymer-based hydrogel substrates (see paragraphs [0010] and [0056]). Regarding claims 1 and 35, Healy teaches the polymer-based substrate contains crosslinking agents (reads on “gelling agent”) and that the stem cells can be encapsulated within the polymer-based substrate during its synthesis (reads on “suspending”) (see paragraph [0242]). Regarding claims 1 and 35, Healy teaches that cells can be in the gel for more that two days (see paragraphs [0027]-[0028] and [0033]-[0035]). Regarding claims 1 and 35, Healy teaches an exemplary embodiment, the polymer-based substrate has a shear modulus of about 100 Pa to 5 kPa, and that the mechanical properties including the shear modulus can be manipulated (reads on “growth modulating factor”) to manipulate the stem cell growth, differentiation, and rates of growth and differentiation (see paragraphs [0227] – [0241]); Regarding claim 37, this teaching of exposing Healy’s cells suspended in the gel to a factor that shifts the shear modulus of the gel to manipulate the stem cell growth, differentiation, and rates of growth and differentiation reads on “exposing the gel to a growth modulating factor”, “wherein the exposing the gel matrix to a growth modulating factor step is after the suspending step”.
Regarding claims 1-3 and 35, Healy teaches that one of the factors that can be used to manipulate the shear modulus is temperature (reads on “growth modulating factor”) (see paragraphs [0227] – [0241]). Regarding claim 3, any pressure level present, including atmospheric pressure, reads on “pressure”. Since Healy does not teach carrying out the method in the absence of pressure, Healy’s teachings read on the limitation of pressure.
Regarding claim 4, Healy teaches medium comprising growth factors can be added to the polymer-based substrates (reads on “induction medium”) to facilitate growth and differentiation of the cells (see paragraphs [0062], [0063] and [0291]). Regarding claim 37, this teaching of exposing Healy’s cells suspended in the gel to a media comprising factors that facilitate growth and differentiation of the cells reads on “exposing the gel to a growth modulating factor”, “wherein the exposing the gel matrix to a growth modulating factor step is after the suspending step”.
Regarding claim 5, Healy teaches that the exposure to the change in temperature, or other modulators, can increase the shear modulus of the gel such that it can mimic the native matrix surrounding stem cells (see paragraphs [0227] – [0241]).
Regarding claim 6, Healy teaches the material with the stem cells bound thereto can be shifted from the first state in which the cell population is essentially non-differentiated into the second state, more closely mimicking an ECM, inducing the stem cells to commit to a lineage (see paragraphs [0227] – [0241]).
Regarding claim 7, Healy teaches fibrinogen may be used in the polymer-based substrate (see paragraph [0168]).
Regarding claim 11, Healy substrate with encapsulated cells reads on being “3-dimensional”.
Regarding claim 12, Healy teaches the that the medium supporting the cells may comprise fetal bovine serum (FBS) (see paragraphs [0291] and [0326]).
Regarding claim 13, Healy teaches a protease inhibitor, e.g., methylsulfonylfluoride (PMSF) may be included in any of the steps to inhibit proteolysis (see paragraph [0154]).
Regarding claim 14, Healy teaches the polymer-based substrate has a shear modulus of about 100 Pa to 5 kPa, and that the shear modulus of the gel can be selected such that it can mimic the native matrix surrounding stem cells (see paragraphs [0227] – [0241]).
Regarding claims 15 and 36, Healy teaches in an exemplary embodiment, the polymer-based substrate comprises and adhesion peptide from ECM molecules (reads on adhesion protein), including collagen (reads on wherein the gelling agent comprises collagen as collagen is part of the hydrogel) (see paragraphs [0009], [0012], [0065], [0071], [0080] and [0235] – [0237]).
Regarding claim 16, Healy teaches the ECM components in the polymer-based substrate may include collage and fibronectin (see paragraph [0065]).
Healy teaches their composition is useful for methods including chemotherapy agent delivery and cell transplantation (see paragraph [0071]).
Healy does not exemplify using all the features that Healy teaches are useful in Healy’s methods. Healy does not teach the cells are arrested in the cell cycle (claims 1 and 35).
Regarding claims 1, 30 and 35, Weissman teaches that mesenchymal stem cells can be treated with an agent to induce quiescence (reads on arrested in the cell cycle) in order to reduce the killing of stem cells by anti-proliferative agents, which is useful in methods involving chemotherapy and cell transplantation (see abstract and paragraphs [0001], [0002] and [0087]).
A person of ordinary skill in the art would have had a reasonable expectation of success in using MSCs as the stem cells in Healy’s method because Healy specifically highlights that MSCs can be used in the methods. The skilled artisan would have been motivated to use MSCs as the stem cells in Healy’s method because Healy specifically teaches that these are a preferred type of stem cell and that they are useful since they are capable of differentiating into various cell lineages (see paragraph [0056]).
A person of ordinary skill in the art would have had a reasonable expectation of success in using the ECM components and ECM mimicking rigidities, including those of 250 Pa, in Healy’s method because Healy specifically that ECM components and ECM mimicking rigidities, including ranges that overlap with 250 Pa, can be used in the methods. The skilled artisan would have been motivated to use ECM components and ECM mimicking rigidities in Healy’s method because Healy specifically teaches that it is useful to mimic the native matrix surrounding stem cells and that it is useful to mimic the ECM of the cell type which the stem cell is differentiating into.
A person of ordinary skill in the art would have had a reasonable expectation of success in including the supporting media additives such as protease inhibitors, serum, and growth factors in Healy’s method because Healy specifically highlights that each of these are useful to include. The skilled artisan would have been motivated to include the supporting media additives such as protease inhibitors, serum, and growth factors in Healy’s method because Healy exemplifies the inclusion of serum and growth factors are useful for Healy’s methods, and Healy teaches that a protease inhibitor may be included in any of the steps to inhibit proteolysis.
It would have been obvious to combine Healy and Weissman to treat Healy’s cells with Weissman’s agent to induce quiescence, and to suspend said quiescent cells in Healy’s composition such that they are in a quiescent state after said suspension. A person of ordinary skill in the art would have had a reasonable expectation of success in treat Healy’s cells with Weissman’s agent to induce quiescence, and to suspend said quiescent cells in Healy’s composition, because Weissman teaches mesenchymal stem cells can be treated with the agent to induce quiescence and teaches cells are suspended in Healy’s composition. The skilled artisan would have been motivated to treat Healy’s cells with Weissman’s agent to induce quiescence because Weissman teaches that the agent can be useful to reduce the killing of stem cells by anti-proliferative agents, when the cells are used for methods such as chemotherapy and cell transplantation. It is noted that none of the claims limit to the cells being quiescent or arrested in the cell cycle prior the “exposure” step, nor do the claims exclude any agents known to cause quiescence from the gel during the suspending step.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claim 9 remains rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Healy et al (US PGPUB 20070026518) in view of Weissman (US PGPUB 20040171559) as applied to claims 1-7, 11-16, 30 and 35-37 above, and further in view of Ju et al (2007, Biomaterials 28 (2007) 2097–2108).
The teachings of Healy in view of Weissman are discussed and relied upon above.
Healy does not teach the source or the amount of the fibrinogen.
Ju is drawn to teachings of gels made from fibrinogen/fibrin, and Ju teaches cells can be embedded within fibrin gels since the polymerization process is non-toxic, making fibrin an attractive scaffold for transplanted cells (see abstract). Regarding claim 9, Ju teaches the gels are made with 3 mg/ml fibrinogen (see col. 2 on page 2098). Regarding claim 9, Ju teaches gels made from fibrinogen from mammalian sources degrade rapidly and may be contaminated with blood-borne pathogens such as HIV, hepatitis C, and prion, and therefore it is useful to look to other species for a source of fibrinogen (see col. 1 on page 2098). Regarding claim 9, Ju teaches the fibrin proteins from salmon fibrinogen (reads on heterothermic animal) gels more resistant to proteolysis than those made from mammalian fibrins (see col. 2 on page 2106).
It would have been obvious to combine Healy and Ju to use salmon fibrinogen as the fibrinogen in Healy’s hydrogel. A person of ordinary skill in the art would have had a reasonable expectation of success in using 3 mg/ml salmon fibrinogen as the fibrinogen in Healy’s hydrogel because Ju establishes that 3 mg/ml salmon fibrinogen can be used to make gels that support cells. The skilled artisan would have been motivated to use salmon fibrinogen as the fibrinogen in Healy’s hydrogel because Ju highlights that there are numerous advantages to salmon as a source of fibrinogen compared to mammals that are conventional sources of fibrinogen.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Claim 31 remains rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Healy et al (US PGPUB 20070026518) in view of Weissman (US PGPUB 20040171559) as applied to claims 1-7, 11-16, 30 and 35-37 above, and further in view of Jain et al (US PGPUB 20060140914).
The teachings of Healy in view of Weissman are discussed and relied upon above.
Healy is silent as to if the collagen is type-I collagen.
Regarding claim 31, Jain teaches that type-I collagen, together with fibronectin, is useful for making gels that support mesenchymal stem cells (see paragraph [0116]).
It would have been obvious to combine Healy and Jain to use that type-I collagen, together with fibronectin, in Healy’s hydrogel. A person of ordinary skill in the art would have had a reasonable expectation of success in using type-I collagen as the collagen in Healy’s hydrogel because Jain teaches that type-I collagen, together with fibronectin, is useful for making gels that support mesenchymal stem cells. The skilled artisan would have been motivated to use type-I collagen as the collagen in Healy’s hydrogel because while Healy teaches that both collagen and fibronectin are useful in the gel, Healy does not disclose what type of collagen should be used and this deficiency is made up by the Jain reference.
Therefore, the invention as a whole would have been prima facie obvious to a person of ordinary skill at the time the invention was made.
Response to Arguments
Applicant's arguments filed 7/21/25 have been fully considered but they are not persuasive.
Applicant highlights that Ozbas discloses seeding quiescent cells, cells that are arrested in the cell cycle, in the gel. Applicant then alleges that Ozbas does not teach the limitation wherein the "mesenchymal stem cells exhibit a rounded morphology or are arrested in a cell cycle after the initial step of suspending in a gel matrix" because Ozbas’ cells were also in a quiescent state prior to the suspending step. However, as stated in the above rejection and acknowledged by applicant, Ozbas discloses seeding quiescent cells (reads on “arrested in the cell cycle”) and therefore Ozbas’ suspended quiescent cells read on the limitation of “arrested in a cell cycle after the initial step of suspending in a gel matrix”. Applicant should also note that the limitation of “after the initial active step of suspending” is broad to include any time point after the initial active step of suspending begins. Furthermore, none of the claims limit to the cells not being quiescent or arrested in the cell cycle prior the “suspending” step. Therefore this argument is not persuasive. Furthermore, applicant is reminded that the claims limit to two options, (1) cells exhibit a rounded morphology after the initial step of suspending, or (2) are arrested in a cell cycle after the initial step of suspending. As stated in the rejection, Ozbas also specifically shows that cells in the gel have a rounded morphology after being suspended in the gel (see Figure 29 as cited in the rejection above) and therefore Ozbas’ teachings also read on the other option in the independent claims.
Applicant highlights that Healy provides examples of polymer-based hydrogel substrates which include covalently grafted growth factors or differentiation factors. Applicant then highlights that the instant claim limits to a method comprising two steps, a step of suspending the mesenchymal stem cell in a gel matrix and a step of exposing the gel matrix to a growth modulating factor. As an initial matter, it is noted that only amended claim 37 limits to the “exposing” step taking place after the “suspending” step. As stated in the above rejection, Healy teaches an exemplary embodiment, wherein the mechanical properties including the shear modulus of the gel comprising suspended cells can be manipulated to manipulate the cell’s growth, differentiation, and rates of growth and differentiation. Therefore, as stated above, this teaching of exposing Healy’s cells suspended in the gel to a factor that shifts the shear modulus of the gel to manipulate the cell’s growth, differentiation, and rates of growth and differentiation reads on “exposing the gel to a growth modulating factor”, “wherein the exposing the gel matrix to a growth modulating factor step is after the suspending step”. Furthermore, as stated in the rejection, Healy also teaches medium comprising growth factors can be added to the gels comprising the suspended cells to facilitate growth and differentiation of the cells, and this teaching of exposing Healy’s cells suspended in the gel to a media comprising factors that facilitate growth and differentiation of the cells also reads on “exposing the gel to a growth modulating factor”, “wherein the exposing the gel matrix to a growth modulating factor step is after the suspending step”. Therefore these arguments are not persuasive.
Conclusion
No claims are free of the art. 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 Stephanie McNeil whose telephone number is (571)270-5250. The examiner can normally be reached Monday - Friday 9:30am - 5:30pm.
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 Landau can be reached at 5712720614. 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.
/S.A.M/ Examiner, Art Unit 1653
/SHARMILA G LANDAU/ Supervisory Patent Examiner, Art Unit 1653