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 .
Status of the Claims
Claims 1-3, 7-8, 11, 13-14, 25-26, 30-32, and 34-39 are pending.
Claims 1-3, 7-8, 11, 13-14, 25-26, 30-32, and 34-39 have been examined on their merits.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-3, 7-8, 11, 13-14, 25-26, and 30 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Masunaga et al. (US 5,714,461A, 1998) as evidenced by Levi et al. (Expert Review of Hematology, 2018), Patel et al. (Clinical and Applied Thrombosis/Hemostasis, 2019), and ZenBio (Human Dermal Fibroblast Manual, 2016).
In regards to claim 1, Masunaga discloses methods for treating blood coagulation disorders (coagulopathies, and therefore, reducing coagulopathy) comprising administering to afflicted subjects a therapeutically effective amount of the protein tumor cytotoxic factor II (TCF-II) (claim 1; which is noted is a historic name for hepatocyte growth factor (HGF)) derived from fibroblasts (column 1, lines 5-12; column 3, lines 62-64). The instant specification explicitly states that proteins, including growth factors, are an example of a fibroblast derivative (instant paragraph [0019]).
In regards to claims 2-3, Masunaga discloses that the coagulopathy can be disseminated intravascular coagulation (DIC) (claim 7).
As evidenced by Levi, DIC is associated with elevated levels of tissue factor (also referred to as Factor III, which is a protein that initiates coagulation in damaged tissues) in at least monocytes (Triggers of coagulation activation in DIC, p3).
In regards to claims 7-8, 11, as above, Masunaga discloses that the coagulopathy can be disseminated intravascular coagulation (DIC) (claim 7).
As evidenced by Levi, DIC is associated with downregulation of endothelial thrombomodulin (Propagation of coagulation activation in DIC, p4). It is well-known in the art that thrombomodulin is both an anticoagulant and is expressed on the surface of endothelial cells.
In regards to claim 13, as above, Masunaga discloses that the coagulopathy can be disseminated intravascular coagulation (DIC) (claim 7)
As evidenced by Patel, DIC is associated with inflammation (Abstract, p1).
In regards to claim 14, as above, Masunaga discloses that the coagulopathy can be disseminated intravascular coagulation (DIC) (claim 7).
As evidenced by Patel, DIC-associated inflammation is associated with a 50% or more increase in TNFα compared to controls (Fig. 1, p4).
In regards to claim 25, as evidenced by ZenBio, fibroblasts double in the range of 18-24 hours (p6).
In regards to claims 26 and 30, whether the fibroblasts decrease the ability of responding T cells to proliferate in a mixed lymphocyte reaction, and wherein the decrease is more than 20% as in claim 30, is a property of fibroblasts, not active method steps. In particular, claim 26 does not require steps of performing a mixed lymphocyte reaction and does not require steps of contacting fibroblasts with T cell. In the instant case, because Masunaga discloses coagulopathies with fibroblast-derived growth factors as discussed above, these fibroblasts are deemed to have the ability to decrease T cell proliferation if in a mixed lymphocyte reaction, absent evidence to the contrary.
Therefore, Masunaga anticipates the invention as claimed.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 31 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Masunaga et al. (US 5,714,461A, 1998) in view of Kajihara et al. (Fertility and Sterility, 2011) and Salvemini et al. (Free Radical Biology and Medicine, 2002).
Masunaga anticipates claim 1 as discussed above.
In regards to claim 31, Masunaga does not explicitly teach that the fibroblasts were treated with human chorionic gonadotropin (hCG).
However, Kajihara teaches that contacting endometrial stromal cells (endometrial fibroblasts) with hCG confers protection against oxidative stress-induced apoptosis (Abstract, p1302; Fig. 1, p1303). As further taught by Salvemini, oxidative stress is a cause of pathology in DIC and in particular, endotoxic and hemorrhagic shock, and in endothelial injury associated with DIC syndrome (Abstract, p1173; Role of Free Radicals in Disseminated Intravascular Coagulation Syndrome, p1177-1180).
Therefore, a person of ordinary skill in the art would have been motivated to treat fibroblasts with hCG in order to protect them from oxidative stress-induced apoptosis at sites of injury of coagulopathies such as DIC.
Furthermore, because Kajihara teaches that fibroblasts can be contacted with hCG and survive in oxidative-stressed conditions (Fig. 1, p1303; Fig. 3, p1304), it could have been done with predictable results and a reasonable expectation of success.
In regards to augmenting immune modulatory activity, this a property of fibroblasts when contacted with hCG, and the method of Masunaga when contacted with hCG as suggested by Kajihara would be expected to have this property. Furthermore, because Kajihara teaches that hCG is known to increase levels of leukemia inhibitory factor (LIF, a known immune factor; p1306, right column, middle paragraph), augmenting immune modulatory activity would have been the expected result.
In regards to claim 32, Kajihara teaches that fibroblasts can be contacted with concentration of hCG ranging from 0.01 IU/mL to 1 IU/mL (Figure 1, p1303).
While it is unclear what the concentration of 0.01 IU/mL to 1 IU/mL would be when converted to “Molar per 1 million”, a person of ordinary skill in the art could have arrived at a concentration of 1 nano Molar to 1 micro Molar per 1 million fibroblasts or at a concentration of 10 nano Molar to 100 nano Molar per 1 million fibroblasts by routine optimization, and the disclosure does not point to a criticality in this range.
In regards to routine optimization, MPEP § 2144.05(II)(A) states generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.).
In the instant case, because Kajihara teaches that fibroblasts can be cultured with a range of concentrations of hCG (Figure 1, p1303), a person of ordinary skill in the art could have arrived at the broad concentrations in claim 32 by routine optimization with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Masunaga, Kajuhara, and Salvemini renders the invention unpatentable as claimed.
Claims 1, 34-35, and 37-38 are rejected under 35 U.S.C. 103 as being unpatentable over Masunaga et al. (US 5,714,461A, 1998) in view of Postletwaite et al. (Journal of Experimental Medicine, 1990).
Masunaga anticipates claim 1 as discussed above.
In regards to claims 34 and 37-38, Masunaga does not explicitly teach that the fibroblasts were activated with a growth factor such as TNF-α.
However, a person of ordinary skill in the art would have been motivated to contact fibroblasts with a cytokine such as TNF-α because Postletwaite teaches that TNF-α promotes fibroblast migration (Abstract, p1749; Fig. 1, p1750; Table 3, p1752). Furthermore, because Postletwaite demonstrates that fibroblasts can be effectively cultured in vitro with TNF-α (Fig. 1, p1750; Table 3, p1752; Materials and Methods, p1749), it could have been done with predictable results and a reasonable expectation of success.
In regards to claim 35, Postletwaite teaches that TNF-α at a concentration of about 10 pM promoted fibroblast mobilization (Fig. 1, p1750). As Postletwaite performs chemotaxis assays (Fig. 1, p1750), a person of ordinary skill in the art would have recognized that this requires a timing of at least a second.
While it is unclear what the concentration of 10 pM would be when converted to seeding density (i.e., “per million fibroblast cells” as in claim 35), a person of ordinary skill in the art could have arrived at a broad concentration range of 0.1 pg to 20 ng of TNFα per million fibroblast cells by routine optimization, and the disclosure does not point to a criticality in this range.
In regards to routine optimization, MPEP § 2144.05(II)(A) states generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.).
In the instant case, because Postletwaite teaches that fibroblasts can be contacted with TNFα over a wide concentration range of 1 pm to 500 pM (Fig. 1, p1750), a person of ordinary skill in the art could have arrived at a concentration of 0.1 pg to 20 ng TNFα per million fibroblast cells by routine optimization with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Masunaga and Postletwaite renders the invention unpatentable as claimed.
Claims 1 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Masunaga et al. (US 5,714,461A, 1998) in view of O’Heeron et al. (WO2019125996A1, published 06/27/2019).
Masunaga anticipates claim 1 as discussed above.
In regards to claim 36, Masunaga does not explicitly teach that the fibroblast derivative (protein) comprises conditioned media, however, a person of ordinary skill in the art would have been motivated to utilize conditioned media because O’Heeron teaches that conditioned media from fibroblasts can be mitogenic for other cells (paragraph [0020]), can be stored for later use (paragraph [0027]), and can be used for the treatment of disease (paragraph [0032]). Furthermore, because O’Heeron teaches that fibroblast-derived conditioned media can be administered to patients (claim 9; paragraph [0028]) for the treating of inflammatory diseases (such as the coagulopathy DIC) (claim 10) and can comprise growth factors and cytokines (such as HGF) (claims 11), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Masunaga and O’Heeron renders the invention unpatentable as claimed.
Claims 1, 37, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Masunaga et al. (US 5,714,461A, 1998) in view of Gospodarowicz (Nature, 1974).
Masunaga anticipates claim 1 as discussed above.
In regards to claims 37 and 39, Masunaga does not explicitly teach that the fibroblasts were activated with a growth factor such as FGF-1.
However, a person of ordinary skill in the art would have been motivated to contact fibroblasts with a growth factor such as FGF-1 because Gospodarowicz teaches that pituitary-derived FGF (FGF-1), promotes fibroblast proliferation (Fig. 1, p124). Furthermore, because Gospodarowicz teaches that fibroblasts can be effectively cultured in vitro with FGF-1 (Fig. 1, p124), it could have been done with predictable results and a reasonable expectation of success.
Therefore, the combined teachings of Masunaga and Gospodarowicz renders the invention unpatentable as claimed.
Conclusion
No claims are allowed.
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/JOSEPH PAUL MIANO/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631