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 1-5, 7-13 and 20 are pending in this application and were examined on their merits.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 03/09/2026 has been entered.
Response to Amendment
The Declaration under 37 CFR 1.132 filed 03/09/2026 is insufficient to overcome the rejection of claims 1-5, 7-13, 15, 16 and 20 based upon 35 U.S.C. § 103 as set forth in the last Office action because:
The Declarant argues that Du utilizes full-term placental tissues which are outside the claimed range of “not less than 11 weeks and not more than 12 weeks” (Declaration, Pg. 2, #11).
This is not found to be persuasive for the following reasons, in response to Declarant's arguments against the Du reference individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this instance, Zhang et al. teaches the advantages (i.e., containing a greater amount of bioactive proteins/growth factors) of utilizing pre-term placenta with a gestational term of 8.5-12.5 weeks which encompasses the claimed range, such that one of ordinary skill in the art would have found obvious the modification of Du in view of Zhang as set forth in the prior action and below.
The Declarant argues that Zhang describes a relative increase in gross growth factor quantity but does not recognize the profile of growth factors and the ratios of concentration thereof (Declaration, Pg. 2, #12).
This is not found to be persuasive for the following reasons, in response to Declarant's argument that the reference fails to show certain features of the invention, it is noted that the features upon which Declarant relies (i.e., ratios of concentration of the growth factors in the profile) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Zhang only discusses an overall general increase of growth factors present in pre-term placenta, and is silent with regard to the particular concentrations of the growth factors in cultivated XX- or XY-placenta explants or conditioned media thereof. However, the concentration of growth factors in the cultivated XX - or XY-placenta explants and/or placenta explant conditioned media is a result-effective variable dependent upon the length of time the explants are cultured and allowed to secrete growth factors into the surrounding medium and/or the amount/types of growth factors naturally present in the cells/explant. Therefore, the determination of the optimal or workable ranges of the various growth factors by routine experimentation and optimization of result effective variables is not inventive. In this instance, the amount of bioactive proteins (growth factors) which can be used to generate conditioned medium would be dependent on the source placenta, the cells out-migrating therefrom and time conditioning the medium in which the placental explant resides. Those of ordinary skill in the art before the effective filing date on the instant invention would have been motivated to make this modification in order to obtain an effective amount of growth factors in a conditioned medium.
There would have been a reasonable expectation of success in making this modification because the reference already teaches cultivating the same placental explants as claimed and generating conditioned medium therefrom and the determination of result effective variables (e.g. a specific desired concentration of particular growth factors) by routine optimization and experimentation is within the purview of those of ordinary skill in the art.
The Declarant argues that Du and Zhang diverge as Du describes culturing placental tissue under hypoxic conditions while Zhang is drawn to decellularized placental tissue. Declarant notes that decellularized tissue cannot produce growth factors as all cell have been removed (Declaration, Pg. 2, #13).
This is not found to be persuasive for the following reasons, the Examiner’s rationale for a finding of obviousness is not that the method of Du be modified in view of Zhang to use "decellularized preterm placental tissue" but merely that Du be modified to use preterm placental tissue in culturing to obtain the greater amount of beneficial bioactive proteins (growth factors) than contained in full term placenta.
The Declarant argues that a benefit of the claimed invention is the cumulative interaction of all bioactive proteins in the ratio of concentrations (Exhibit C) which are at least in part a function of the gestational term (Declaration, Pg. 2, #14).
This is not found to be persuasive for the following reasons, Exhibit C seems to be nothing more than a restatement of the current claims and does not provide any new data or information. The Examiner further notes that the Declarant admits that the bioactive proteins, concentrations and ratios thereof is at least in part due to the gestational term, which is further supportive of the Examiner’s position to replace the full-term placenta of Du with the pre-term placenta of Zhang.
The Declarant argues that Du uses a standard cultivation technique wherein cells are harvested when confluence reaches 80-90% and it is not apparent that the cultivation or harvest steps were selected to produce any notable technical outcomes. Declarant again notes that Du is drawn to normoxic and hypoxic culture. Declarant asserts that the area taken up by out-migrating/proliferating cells would not be subject to routine optimization, there is no suggestion in the reference to alter from the described methodology and cease migration/proliferation before confluence or that such a deviation would be beneficial (Declaration, Pgs. 2-3, #15).
This is not found to be persuasive for the following reasons, while the reference may teach harvest at a certain percent confluence, the Examiner’s rationale was not based on cell confluence at all. The Examiner set forth rationale both in the prior action and below explaining why the area surrounding an explant taken up by cell migrating from the explant and proliferation would be a result-effective variable based on the length of time the explants are cultured and the amount of cells present in the explant.
Thus, the ordinary artisan would have recognized that the Examiner's basis for rejection is not based on cell confluency but on the area around an explant taken up by cells out-migrating from the explant and proliferating around it.
The Declarant argues that the only proteins monitored by Du were Hif-1α and IL-10 during normoxia and hypoxia while Zhang only describes exemplary growth factors which are not completely co-extensive with those claimed (Declaration, Pg. 3, #16-17).
In response to Declarant's arguments against the Du reference individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this instance, Du was not cited for any monitoring of any particular protein but for its’ method of isolating placental mesenchymal stem cells from placental tissue explants and the preparation and use of conditioned medium therefrom. Zhang was cited for its’ teaching that pre-term placenta of a gestation term of 8.5-12.5 weeks contain a greater amount of bioactive proteins (growth factors, including non-limiting exemplars some of which are also claimed, see Paragraph [0040]) than full term tissue.
The Declarant argues that the content of bioactive proteins and ratios of concentrations thereof is dependent on gestational age with expression generally occurring during pre-term (Declaration, Pg. 3, #18).
This is not found to be persuasive for the following reasons, the Examiner further notes that Declarant admits that the bioactive proteins, concentrations and ratios thereof is at least in part due to the gestational term, which is further supportive of the Examiner’s position to replace the full-term placenta of Du with the pre-term placenta of Zhang. The Examiner notes that Zhang specifically recognizes that pre-term placenta may contain more growth factors than full-term placenta, see Paragraphs [0039]-[0040].
The Declarant argues that as mesenchymal stem cells proliferate and approach senescence their secretion profile shifts and various environmental factors also affect the secretome. Thus bioactive proteins such as growth factors are not universally present in large quantities throughout all of the proliferative stages and their presence is highly dependent on the passage number and environmental cues (Declaration, Pgs. 3-4, #20).
This is not found to be persuasive for the following reasons, if the Declarant is suggesting that the prior art is subject to unpredictability than the instant invention is also subject to the same unpredictability. As Zhang specifically recognizes that pre-term placenta may contain more growth factors than full-term placenta, see Paragraphs [0039]-[0040], the art at least generally recognizes that there is some predictability in terms of expression/secretion of bioactive growth factors and the gestational age of the placenta.
Thus, the concentration of growth factors in the cultivated XX - or XY-placenta explants and/or placenta explant conditioned media is a result-effective variable dependent upon the length of time the explants are cultured to secrete growth factors into the medium and the amount of growth factors naturally present in the explant. Therefore, the determination of the optimal or workable ranges of the various growth factors by routine experimentation and optimization of result effective variables is not inventive.
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.
Claims 1-5 and 7-13 are rejected under 35 U.S.C. § 103 as being
unpatentable over Du et al. (2016), in view of Zhang et al. (CA 3169512 A1), Peled et
al. (WO 2013/121427 A1), Horowitz et al. (2004) and Noble et al. (WO 93/18064), all of
record.
Du et al. teaches a method comprising making placental tissue explants from full-
term newborns and cultivating until placental mesenchymal stem cells (PMSC) move
(migrate) out of the explants (Pg. 52, Column 1, Lines 5-20);
culturing the cells to obtain a conditioned medium (Pg. 52, Column 1, Lines 30- 31 and Column 2, Lines 1-7;
and wherein the conditioned medium protects against scar formation and the reference suggests the use of the composition as a wound therapy (Pg. 51, Abstract), and reading on Claim 1, steps (i), (ii) and (iii).
Du et al. does not teach a method wherein the placenta are XX or XY from a gestational term of not less than 11 week and not more than 12 weeks; wherein the explants are cultivated in a conditioned medium until cell migration and proliferation reaches an area of not more than 4 cm² around the explant;
wherein the conditioned medium is filtered and a proteolysis inhibitor added; wherein the concentration of bioactive proteins in the conditioned medium is controlled;
wherein the conditioned medium is added to the ingredients of an anti-aging cosmetic compositions;
or wherein the concentration of bioactive proteins anti-ageing cosmetic compositions is controlled, as required by Claim 1;
wherein the pre-term placenta is from a medical pregnancy termination, as required by Claim 2;
wherein the placenta explant cultivation stops immediately when cell migration and proliferation reaches an area of not more than 4 cm2 around the explant, as required by Claim 3,
wherein the concentration of bioactive proteins in XY placenta conditioned medium is, as measured by ELISA, EGF from 10 to 18 pg/ml; FGF-7 from 74 to 300 pg/ml; HGF from 941 to 2039 pg/ml; TNF-alpha from 340 to 521 pg/ml; IGF-1 from 630 to 928 ng/ml; VEGF-A from 12 to 38 ng/ml; SCF from 15.5 to 24 ng/ml; TGF- beta 1 from 66.5 to 178 ng/ml; ANGPT1 from 94 to 170 ng/ml; bFGF from 58 to 97 ng/ml, as required by Claims 7 and 15;
wherein the concentration of bioactive proteins in XX placenta conditioned medium is, as measured by ELISA, EGF from 8 to 18 pg/ml; FGF-7 from 90 to 265 pg/ml; HGF from 30 to 104 pg/ml; TNF-alpha from 340 to 546 pg/ml; IGF-1 from 514 to 681 ng/ml; VEGF-A from 16 to 39 ng/ml; SCF from 7.5 to 12 ng/ml; TGF-beta 1 from 311 to 550 ng/ml; ANGPT1 from 104 to 156 ng/ml; bFGF from 14 to 43 ng/ml, as required by Claims 8 and 16;
wherein the ingredients of the anti-ageing cosmetic compositions are compatible with the bioactive proteins and do not destroy them, as required by Claim 9;
wherein the concentration of bioactive proteins in XY of the placenta explants in the anti-ageing cosmetic compositions is, as measured by ELISA, not less than: EGF 1.0 pg/ml; FGF 7-7.4 pg/ml; HGF 94.1 pg/ml; TNF-alpha 34.0 pg/ml; IGF-1 63.0 ng/ml; VEGF-A 1.2 ng/ml; SCF 1.6 ng/ml; TGF-beta 1-6.7 ng/ml; ANGPT1 9.4 ng/ml; bFGF 5.8 ng/ml, as required by Claim 10;
or wherein the concentration of bioactive proteins in XX of the placenta explants in the anti-ageing cosmetic compositions is, as measured by ELISA, not less than: EGF 0.8 pg/ml; FGF 7-9.0 pg/ml; HGF 3.0 pg/ml; TNF-alpha 34.0 pg/ml; IGF-1 51.4 ng/ml: VEGF-A 1.6 ng/ml; SCF 0.8 ng/ml; TGF-beta 1-31.1 ng/ml; ANGPT1 10.4 ng/ml; bFGF 1.4 ng/ml, as required by Claim 11.
Zhang et al. teaches that pre-term placenta of a gestation term of 8.5-12.5 weeks (overlapping the claimed range of not less than 11 and not more than 12 weeks) contain a greater amount of bioactive proteins (growth factors) than full term tissue (Fig. 2 and Pg. 9, Paragraph [0039]).
Peled et al. teaches a method of preparing a conditioned culture medium from a population of placental mesenchymal stem cells (MSC) (Pg. 57, Claims 1 and 6); wherein the conditioned medium is concentrated (Pg. 59, Claim 24); and a cosmetical composition of the conditioned medium and a cosmetically acceptable excipient, diluent or carrier (Pg. 59, Claim 27 and Pg. 60, Claim 31); wherein the conditioned medium can include additional components such as anti-bacterial or anti-fungal agents or is processed by heating before use or storage (see Horowitz et al. below) (Pg. 22, Lines 14-19);
wherein the conditioned medium is filtered to remove large particulates, such as cell debris (and therefore much larger components such as whole cells and tissue) and concentrated (thereby "controlling" the concentration of bioactive proteins therein) (Pg. 38, Lines 16-21);
wherein the composition may be a "cosmeceutical" which may affect the underlying structure of the skin, decrease wrinkle depth, or reverse or ameliorate the effect of photooxidation or aging on the skin. Cosmeceuticals may be particularly useful as skin care products, hair care products, and sun care products. In certain embodiments, cosmeceutical compositions comprise delivery systems including at least one of liposomes, cyclodextrins, polymer systems, or hyaluronic acid or related compounds. Cosmeceutical compositions comprise cosmeceutically-acceptable carriers. The skilled artisan will understand that a pharmaceutically-acceptable. carrier or formulation that is suitable for topical applications will typically also be a cosmeceutically-acceptable carrier or formulation (Pg. 38, Lines 29-32 and Pg. 39, Lines 1-10);
and wherein the methods and compositions of the invention (such as the concentrated conditioned medium) may be directed at achieving a prophylactic benefit. A "prophylactic," or "preventive" effect includes prevention of a condition, retarding the progress of a condition (e.g., skin aging) (Pg. 41, Lines 4-6).
Horowitz et al. teaches that heat treatment can be used to inactivate viruses (Pg. 168, Table 6a).
Noble et al. teaches the addition of inhibitors including aprotinin to conditioned medium to inhibit endogenous proteases after collection (Pg. 34, Lines 16-19).
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 obtaining placental explant conditioned medium of Du et al. to use either XX or XY placenta because these are typically the only available options for placenta to be. Those of ordinary skill in the art would have been motivated to select either XX or XY placenta for the tissue explant because of the limited availability of other options. There would have been a reasonable expectation of success in making this modification because there are only a finite number of genetic profiles for placental tissue to have.
It would have been further obvious to those of ordinary skill in the art before the instant invention to cultivate the explants of Du et al. until cell migration and proliferation reaches an area of not more than 4 cm² around the explant and then stopped immediately, because while the Du et al. teaches cultivating until placental mesenchymal stem cells (PMSC) move (migrate) out of the explants, the reference is silent with regard to the area the migrating cells take up around the explant before stopping the cultivation. The area taken up by migrating/proliferating cells is a result- effective variable dependent upon the length of time the explants are cultured and the amount of cells present in the explant. Therefore, the determination of the optimal or workable ranges of the area the migrating/proliferating explant cells take up around the explant before stopping cultivation by routine experimentation and optimization of result effective variables is not inventive. In this instance, the area around the explant taken up by migrating/proliferating cells is a reflection of the amount of cells surrounding the explant which can be used to generate conditioned medium.
Those of ordinary skill in the art before the effective filing date on the instant invention would have been motivated to make this modification in order to obtain an effective number of cells to generate a conditioned medium. There would have been a reasonable expectation of success in making this modification because the reference already teaches cultivating explants until the desired cells migrate out of the explant and the determination of result effective variables (e.g. a specific area the migrating/proliferating cells take up around the explant before stopping cultivation) by routine optimization and experimentation, is within the purview of those of ordinary skill in the art.
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 obtaining full-term placental explant conditioned medium of Du et al. to use the pre-term placenta of Zhang et al. in place of the full-term placenta because of the beneficial aspects of pre-term placenta. Those of ordinary skill in the art would have been motivated to make this modification because Zhang et al. teaches that pre-term placenta contains a greater amount of bioactive proteins (growth factors) than full term tissue. There would have been a reasonable expectation of success in making this modification because both references are drawn to the same field of endeavor, that is, the characterization and/or use of placental tissue.
With regard to Claim 3, 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 obtaining pre-term placental explant conditioned medium of Du et al. and Zhang et al. to obtain the pre-term placenta from a medical pregnancy termination because there are only a finite number of ways to obtain pre-term placenta. Those of ordinary skill in the art would have been motivated to make this modification in order to obtain the desired pre-term placenta. There would have been a reasonable expectation of success in making this modification because both references are drawn to the same field of endeavor, that is, the characterization and/or use of placental tissue.
It would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of obtaining pre-term XX or XY placental explant conditioned medium of Du et al. and Zhang et al. (wherein the explants are cultivated in a self-conditioned medium) with the filtration of the conditioned medium, concentration of bioactive proteins in the conditioned medium and addition of the conditioned medium is added to the ingredients of an anti-aging cosmetic compositions, as taught by Peled et al. because of the beneficial aspects of doing SO. Those of ordinary skill in the art would have been motivated to make this modification because Peled et al. removes undesired elements from the conditioned medium, concentrates the conditioned medium (and bioactive proteins therein) and utilizes the conditioned medium to formulate cosmetic anti-ageing compositions.
There would have been a reasonable expectation of success in making this modification because at least Du et al. and Peled et al. references are drawn to the same field of endeavor, that is, the characterization and/or use of placental tissue explant derived conditioned medium as a skin treatment.
With regard to Claim 9, it would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention that the method of obtaining pre-term XX or XY placental explant conditioned medium and addition thereof to the ingredients of an anti-aging cosmetic compositions of Du et al., Zhang et al. and Peled et al., so that the other components of the anti-ageing compositions are compatible with the bioactive proteins in the conditioned medium and do not destroy them, because this would ensure the cosmetic/cosmeceutical composition would comprise active bioactive proteins. Those of ordinary skill in the art would have been motivated to make this modification in order to have a cosmetic/cosmeceutical composition with undegraded bioactive proteins. There would have been a reasonable expectation of success in making this modification because at least Du et al. and Peled et al. references are drawn to the same field of endeavor, that is, the characterization and/or use of placental tissue explant derived conditioned medium as a skin treatment.
It would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of obtaining pre-term XX or XY placental explant derived concentrated conditioned medium cosmetic composition of Du et al., Zhang et al. and Peled et al. to further control the concentration of bioactive proteins in anti-ageing cosmetic compositions because the concentration of the bioactive proteins in the conditioned medium would also concentrate the bioactive proteins in the cosmetic composition to which the conditioned medium is added. Those of ordinary skill in the art would have been motivated to make this modification in order to have a concentration of the desirable elements of the conditioned medium in a cosmetic composition. There would have been a reasonable expectation of success in making this modification because the Peled et al. reference already teach the concentration of the conditioned media (thereby concentrating any bioactive proteins therein), as well as the addition of the conditioned medium to anti- ageing cosmetic compositions. Thus, the bioactive proteins in the concentrated conditioned medium would also be concentrated (controlled) in the anti-ageing cosmetic composition.
It would have been further obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of obtaining pre-term XX or XY placental explant derived concentrated conditioned medium cosmetic composition of Du et al., Zhang et al. and Peled et al. with the addition of the protease inhibitor aprotinin to the conditioned medium as taught by Noble et al. because this would prevent proteolysis by endogenous proteases in the conditioned medium.
Those of ordinary skill in the art would have been motivated to make this modification in order to prevent proteolysis of the bioactive proteins in the placenta conditioned medium. There would have been a reasonable expectation of success in making this modification because at least Du et al., Peled et al. and Noble et al. are all drawn to the same field of endeavor, that is, the preparation of cell conditioned media.
With regard to Claims 4 and 12, Peled et al. teaches a method of preparing a conditioned culture medium from a population of placental mesenchymal stem cells (MSC) (Pg. 57, Claims 1 and 6) wherein the conditioned medium is filtered to remove large particulates, such as cell debris (and therefore much larger components such as whole cells and tissue) and concentrated (thereby "controlling" the concentration of bioactive proteins therein) (Pg. 38, Lines 16-21).
With regard to Claims 5 and 13, Noble et al. teaches the addition of inhibitors including aprotinin to conditioned medium to inhibit endogenous proteases after collection (Pg. 34, Lines 16-19).
With regard to Claims 7, 8, 10 and 11, the references are silent with regard to the concentrations of growth factors in the cultivated XX- or XY-placenta explants and/or placenta explant conditioned media.
However, the concentration of growth factors in the cultivated XX - or XY-placenta explants and/or placenta explant conditioned media is a result-effective variable dependent upon the length of time the explants are cultured to secrete growth factors into the medium and the amount of growth factors naturally present in the explant. Therefore, the determination of the optimal or workable ranges of the various growth factors by routine experimentation and optimization of result effective variables is not inventive. In this instance, the amount and type of bioactive proteins (growth factors) which can be used to generate conditioned medium would be dependent on the source placenta and time conditioning the medium in which the placental explant resides. Those of ordinary skill in the art before the effective filing date on the instant invention would have been motivated to make this modification in order to obtain an effective amount of growth factors in a conditioned medium. There would have been a reasonable expectation of success in making this modification because the reference already teaches cultivating the same placental explants as claimed and generating conditioned medium therefrom and the determination of result effective variables (e.g. a specific desired concentration of growth factors) by routine optimization and experimentation is within the purview of those of ordinary skill in the art.
Claims 1-5 and 7-13 and 20 are rejected under 35 U.S.C. § 103 as being unpatentable over Du et al. (2016), in view of Zhang et al. (CA 3169512 A1), Peled et al. (WO 2013/121427 A1), Horowitz et al. (2004) and Noble et al. (WO 93/18064), as applied to Claims 1-5 and 7-13 above, and further in view of Miao et al. (2006), as evidenced by Aberman (US 2013/0004465 A1), all of record.
The teachings of Du et al., Zhang et al., Peled et al., Horowitz et al. and Noble et al. were discussed above.
None of the above references taught wherein the XX or XY placental explants were taken from the amnion and chorion of the placenta, as required by Claim 20.
Miao et al. teaches that placenta mesenchymal stem cells (PMSC) can be obtained from dissected placenta (thus whole) (Pg. 684, Paragraph 2.1).
Aberman evidences that (whole) placenta includes the amnion and chorion (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 Du et al. comprising
generally making placental tissue explants from full-term newborns and cultivating until
placental mesenchymal stem cells (PMSC) move (migrate) out of the explants to
specifically use explants taken from the amnion and chorion of the placenta because
Miao teaches that PMSC are obtained from the placenta as a whole and Aberman
evidences that the placenta comprises both the amnion and chorion. Thus, the
placenta of Du from which explants are obtained would necessarily contain both amnion
and chorion. Those of ordinary skill in the art would have been motivated to make this
modification in order to provide placental tissue from which explants containing PMSC
can be obtained.
There would have been a reasonable expectation of success in
making this modification because Du generally teaches placental tissue explants and
Miao teaches that PMSC can be obtained from the placenta and the placenta contains
both amnion and chorion.
Response to Arguments
Applicant's arguments filed 03/09/2026 have been fully considered but they are not persuasive.
The Applicant argues that the Examiner’s position is that if a property can be adjusted than it would have been obvious to do so. Applicant notes that a finding of obviousness also concerns motivation. Applicant asserts that did not provide a rationale as to why the ordinary artisan would modify the variable (gestation term and cell migration/proliferation area) through routine optimization and why there would have been a reasonable expectation of success in doing so (Remarks, Pg. 5, Lines 21-28 and Pg. 6, Lines 1-13).
This is not found to be persuasive for the reasoning set forth both above and in the prior action. Initially, the placental gestation term was specifically taught by Zhang and was not subject to optimization rationale in a finding of obviousness.
Secondly, It would have been obvious to those of ordinary skill in the art to cultivate the explants of Du until cell migration and proliferation reaches an area of not more than 4 cm² around the explant and then stopped immediately, because while the Du teaches cultivating until placental mesenchymal stem cells (PMSC) move (migrate) out of the explants, the reference is silent with regard to the area the migrating cells take up around the explant before stopping the cultivation. The area taken up by migrating/proliferating cells is a result-effective variable dependent upon the length of time the explants are cultured and the amount of cells present in the explant and available to out-migrate and proliferate. Therefore, the determination of the optimal or workable ranges of the area the migrating/proliferating explant cells take up around the explant before stopping cultivation by routine experimentation and optimization of result effective variables is not inventive. In this instance, the area around the explant taken up by migrating/proliferating cells is a reflection of the amount of cells surrounding the explant which can be used to generate the desired conditioned medium. Those of ordinary skill in the art would have been motivated to make this modification in order to obtain an effective number of cells to generate a desired conditioned medium. There would have been a reasonable expectation of success in making this modification because the reference already teaches cultivating explants until the desired cells migrate out of the explant and obtaining a conditioned medium therefrom and the determination of result effective variables (e.g. a specific area the migrating/proliferating cells take up around the explant before stopping cultivation) by routine optimization and experimentation, is within the purview of those of ordinary skill in the art.
The Applicant argues that Du does not imply or mention any particular “area” taken up by cells and is therefore not an art-recognized variable. Secondly, Applicant asserts that the Examiner’s rationale that the area taken up by cells out-migration and proliferation from an explant is dependent on time implies the variable is time and area is the result. Applicant notes that if area taken up by cell is the variable that what is the result? (Remarks, Pg. 6, Lines 14-24).
This is not found to be persuasive for the following reasons, as Applicant is no doubt aware, a finding of obviousness does not require that the art recognize the variable as result-effective but merely that the parameter achieve a recognized result. In this instance, the prior art achieves a recognized result of out-migration and proliferation of stem cells from a placental explant from which conditioned medium can be obtained. It is inherent that these cells must take up space/area in the culture after leaving the explant and proliferating. This is the recognized result-effective variable which is dependent on the length of time in which the cells are allowed to out-migrate from the explant and grow/proliferate (thus taking up more space/area) and the amount of cells initially present in the explant (that is, a greater initial number of cells will take up a larger area/space and more growth than a lesser number of cells).
Applicant argues there is no evidence in Du that there is a technical goal or benefit that frows from the area taken up from migrating/proliferating cells or the time to achieve this (Remarks, Pg. 6, Lines 25-28).
This is not found to be persuasive for the following reasons, the result of the area taken up by migrating/proliferating cells is the amount of cells available to produce the desired conditioned medium. Du teaches that this conditioned medium has beneficial aspects (presumably due to the secreting of factors into the medium). Thus, the desired beneficial conditioned medium (the goal or benefit) would flow from the amount of cells available to produce said medium.
The Applicant opines that the ordinary artisan would have no motivation to modify the area variable to produce a result. Applicant again notes that Du does not teach a result that flows from the area taken up by migrating/proliferating cells (Remarks, Pg. 6, lines 29-32 and Pg. 7, Lines 1-2).
This is not found to be persuasive for the following reasons, the prior art achieves a recognized result of out-migration and proliferation of stem cells from a placental explant from which conditioned medium can be obtained. It is inherent that these cells must take up space/area in the culture after leaving the explant and proliferating. This is the recognized result-effective variable which is dependent on the length of time in which the cells are allowed to out-migrate from the explant and grow/proliferate (thus taking up more space/area) and the amount of cells initially present in the explant (that is, a greater initial number of cells will take up a larger area/space and more growth than a lesser number of cells).
Those of ordinary skill in the art would have been motivated to make this modification to allow the out-migrated/proliferating cells to reach a particular area around the explant (determined by routine experimentation and optimization) in order to obtain an effective number of cells to generate a desired conditioned medium.
The Applicant argues that the Examiner’s position that the area surrounding the explant taken up by out-migrating/proliferating cells is a reflection of the amount of cells surrounding the explant which produce the conditioned medium is not supported by evidence. Applicant opines that this is impermissible hindsight and cites the Declaration allegedly disputing the Examiner’s finding, noting that protein expression is, in part, dependent on gestational age and protein amounts fluctuate over time. Applicant asserts the Du only investigates the effects of culture oxygen as a result-effective variable (Remarks, Pg. 7, Lines 11-29).
This is not found to be persuasive for the following reasons, in response to Applicant'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, Du teaches the out-migration of stem cells from placental explants and use thereof to produce a beneficial conditioned medium. It is inherent that these cells must take up space/area in the culture after leaving the explant and proliferating. This is a recognized result-effective variable which is dependent on the length of time in which the cells are allowed to out-migrate from the explant and grow/proliferate (thus taking up more space/area) and the amount of cells initially present in the explant (that is, a greater initial number of cells will take up a larger area/space and more growth than a lesser number of cells). Those of ordinary skill in the art would have been motivated to make the Examiner proposed modification to allow the out-migrated/proliferating cells to reach a particular area around the explant (determined by routine experimentation and optimization) in order to obtain an effective number of cells to generate a desired conditioned medium. Regarding the Declaration, if Applicant is suggesting that the prior art is subject to unpredictability than the instant invention is also subject to the same unpredictability. As Zhang specifically recognizes that pre-term placenta may contain more growth factors than full-term placenta, see Paragraphs [0039]-[0040], the art at least generally recognizes that there is some predictability in terms of expression/secretion of bioactive growth factors and the gestational age of the placenta. Thus, the concentration of growth factors in the cultivated XX - or XY-placenta explants and/or placenta explant conditioned media is a result-effective variable dependent upon the length of time the explants are cultured to secrete growth factors into the medium and the amount of growth factors naturally present in the explant.
Therefore, the determination of the optimal or workable ranges of the various growth factors by routine experimentation and optimization of result effective variables is not inventive.
The Applicant argues that it is not articulated why the ordinary artisan would choose a particular narrow week range from within the pre-term period. Applicant asserts that if mere gross quantity of cells is the goal than there is no motivation to select with the pre-term range and Zhang does not teach a benefit to such a selection, therefore there is no reason to optimize (Remarks, Pg. 8, Lines 12-18).
This is not found to be persuasive for the following reasons, Zhang teaches pre-term placenta (8.5-12.5 weeks) contains a greater amount of bioactive proteins (growth factors) than full-term placenta. The claimed range of 11-12 weeks lies within the prior art disclosed range and thus, is prima facie obvious. See the MPEP at 2144.05, I. It would have been obvious to those of ordinary skill in the art to modify the method of obtaining full-term placental explant conditioned medium of Du et al. to use the pre-term placenta of Zhang et al. in place of the full-term placenta because of the beneficial aspects of pre-term placenta, such as a greater amount of bioactive proteins. Those of ordinary skill in the art would have been motivated to make this modification to obtain a conditioned medium with a greater amount of bioactive proteins therein.
The Applicant argues that the Examiner’s interpretation of Zhang’s gestational term is based on impermissible hindsight. Applicant alleges that the broadest disclosed range in the reference is 1-20 weeks, with a preference toward placental tissue at the lower range. Applicant argues that Fig. 2 of the reference depicting 60 days (about 8.5 weeks) to 88 days (about 12.5 weeks) is not a preferred range and omits reference to 95 days (13.6 weeks) (Remarks, Pg. 8, Lines 19-33 and Pg. 9, Lines 1-2).
In response to Applicant'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, Zhang uses the term “pre-term” placenta at Pg. 9, Paragraph [0039]. At Pg. 6, Paragraph [0027] “preterm placental tissue” is defined as tissue obtained before full-term and at Pg. 8, Paragraph [0034] provides various examples thereof including several which meet, overlap or encompass the claimed gestational range, i.e., about 10 weeks, about 12 weeks, about 1-12 weeks and about 1-10 weeks prior to full term. Contrary to Applicant’s assertion the reference citation shows no particular preference for any range.
Fig. 2 depicts a specific embodiment wherein the greatest amount of measured growth factor was obtained from pre-term placental tissue in the period between 60-88 day, with amounts decreasing following that time (e.g. at 95 days). Thus, the presented data as interpreted by the ordinary artisan would be that the greatest/optimal amount of growth factors is obtained from pre-term placenta within that gestational range.
The Applicant argues that in Fig. 2 of Zhang the error bar shows no statistical difference in protein measurements and therefore no motivation exists to select a particular gestational time range within the pre-term ranges disclosed. Applicant opines that the reference only shows a preference for pre- vs. post-term tissue and does not teach or suggest optimization (Remarks, Pg. 9, Lines 3-17).
This is not found to be persuasive for the following reasons, the data presented in Fig. 2 gives a general indication, if not statistically significant, that the mean amount of growth factor content in pre-term placental tissue is greatest from 60-88 days with mean amounts decreasing following that time (e.g. at 95 days and beyond up to full-term). Thus, the presented data as interpreted by the ordinary artisan would be that the greatest/optimal amount of growth factors is obtained from pre-term placenta within that gestational range and therefore motivation would exist to select placental tissue in that age range.
The Applicant argues that the Examiner’s position that more protein is desirable and that protein quantity increases over time is disputed by the Declaration which indicates that protein expression is dynamic and fluctuates. Applicant concludes that there is no motivation in the references to optimize parameters to arrive at the claimed invention (Remarks, Pg. 9, Lines 18-29 and Pg. 10, Lines 1-8).
Regarding the Declaration, if Applicant is suggesting that the prior art is subject to unpredictability than the instant invention is also subject to the same unpredictability. As Zhang specifically recognizes that pre-term placenta may contain more growth factors than full-term placenta, see Paragraphs [0039]-[0040] and Fig. 2, the art at least generally recognizes that there is some predictability in terms of expression/secretion of bioactive growth factors and the gestational age of the placenta. Thus, the concentration of growth factors in the cultivated XX - or XY-placenta explants and/or placenta explant conditioned media is a result-effective variable dependent upon the length of time the explants are cultured to secrete growth factors into the medium and the amount of growth factors naturally present in the explant. Therefore, the determination of the optimal or workable ranges of the various growth factors by routine experimentation and optimization of result effective variables is not inventive.
The Applicant submits arguments originally filed on 11/19/2025 along with the Declaration submitted herewith (Remarks, Pgs. 10-13).
As the Examiner has previously responded to the Arguments filed 11/19/2026 in the Final Action mailed 12/16/2025 and addressed the Declaration herein, the remarks have not been further treated here.
Conclusion
No claims are allowed.
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims could have been finally rejected on the grounds and art of record in the next Office action if they had been entered in the application prior to entry under 37 CFR 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a request for continued examination and the submission under 37 CFR 1.114. See MPEP § 706.07(b). 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.
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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.
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/PAUL C MARTIN/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
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