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Claims 1-17 are pending in this application, Claims 10-17 are acknowledged as withdrawn, Claims 1-9 were examined on their merits.
The objection to the Specification because of embedded hyperlinks and/or browser executable code has been withdrawn due to the Applicant’s amendments to the Specification filed 07/06/20206.
The objection to the Specification because of improper use of Trademarks has been withdrawn due to the Applicant’s amendments to the Specification filed 07/06/20206.
The objection to Claim 8 because of minor informalities has been withdrawn due to the Applicant’s amendments to the claims filed 07/06/2026.
The rejection of Claim 2 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th
paragraph, as being of improper dependent form for failing to further limit the subject
matter of the claim upon which it depends, or for failing to include all the limitations of
the claim upon which it depends, has been withdrawn due to the Applicant’s amendments to the claims filed 07/06/2026.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9 are rejected under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 now recites, “a step of generating an aggregate of human pluripotent stem cells (hPScs) and trophoblast cells by culturing aggregated hPScs in a medium comprising a MEK inhibitor and a TGF-beta inhibitor”. It is unclear if the culturing of aggregate hPSC is performed with or without trophoblast cells and when the hPSC cells are aggregated, such that the metes and bounds of the claim can be readily ascertained. For example, the claim requires generating “aggregated” cells by culturing “aggregated” cells.
For purposes of examination, the Examiner has construed the limitation as a step of generating an aggregate of human pluripotent stem cells (hPSCs) and trophoblast cells by culturing aggregated hPSC with trophoblast cells in a medium comprising an MEK inhibitor and a TGF-β inhibitor. Claims 2-9 are rejected as being dependent upon rejected Claim 1 and for failing to remedy the indefiniteness thereof.
Claim 7 is rejected under 35 U.S.C. § 112(b) or 35 U.S.C. § 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 7 recites, “the cells”. It is unclear whether the limitation refers to all of the cells recited in amended Claim 1 or just some particularly.
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 1-4, 6, 7 and 9 are rejected under 35 U.S.C. § 103 as being unpatentable over Rivron et al. (US 9,822,336 B2), of record, in view of Babyatsky et al. (1996).
Rivron et al. teaches a method comprising 3D culturing (in a non-adherent
surface microwell) an aggregate of mouse embryonic stem (pluripotent) cells in a first culture medium, wherein the first culture medium comprises a modulator of the MAPK pathway, wherein MAPK is known as ERK (Column 20, Line 25) and a modulator of the TGF pathway (Column 38, Claims 1 and 5);
and then adding trophoblast cells and culturing in a second medium comprising a
modulator of the HIPPO pathway (Column 38, Claims 1 and 5);
wherein a blastocyst-like cell aggregate/blastoid is generated (Abstract);
wherein the modulator of the HIPPO pathway may be an inhibitor, such as GPCR
ligands (lysophosphatidic acid receptor is a GPCR), such as GPR30 ligands, such as
estradiol and tamoxifen (Column 22, Lines 66-67 and Column 23, Lines 1-8);
wherein any combination of modulation (activation or inhibition) is applied (Column 23, Lines 12-15);
wherein the cell types for use in the present invention, such as trophoblast cells,
pluripotent or totipotent cells, can be isolated from natural embryonic structures of any
mammalian animal, in particular a mouse or a rat, and further a horse, cow, pig, sheep,
goat, dog, cat, monkey or human (Column 9, Lines 1-5 and 12-15);
wherein the cell aggregate forms an inner cell mass-like tissue, as well as a
blastocoel (fluid filled blastocyst cavity), together surrounded by a trophectoderm-like tissue and the double layered cell aggregate has a diameter of about 10 µm to 200 µm (Column 15, Lines 8-14);
and wherein the present method for obtaining a blastoid bears high promise for
identifying novel drug targets and enhances the probability of clinical success of new
drugs (Column 33, Lines 47-50), and reading on Claims 1 and 6.
With regard to Claim 1, the reference teaches a medium comprising a modulator of the MAPK pathway, wherein MAPK is known as ERK (Column 20, Line 25) and a modulator of the TGF pathway (Column 38, Claims 1 and 5). Thus, the ordinary artisan would recognize that an MAPK/ERK modulator/inhibitor is also a modulator/inhibitor of MEK as MAPK is the last part of the pathway activated/phosphorylated by MEK.
With regard to Claim 2, the reference teaches the HIPPO pathway modulator/inhibitor can be present in the first and/or second culture medium (Column 38, Claim 5).
With regard to Claim 3, the reference teaches that aggregated mPSC are formed by seeding and culturing in a growth medium comprising a ROCK inhibitor (Column 38, Claims 1 and 4).
With regard to Claim 4, the reference teaches that the seeded mPSC have been treated with a modulator of the PKC pathway, the Wnt pathway and the STAT pathway (Column 38, Claim 5) and wherein any combination of modulation (activation or inhibition) is applied (Column 23, Lines 12-15) and wherein the seeded mPSC cells are allowed to settle and aggregate while multiplying (thus forming a 2D culture).
With regard to Claim 7, the reference teaches the cell aggregate forms an inner cell mass-like tissue, as well as a blastocoel (fluid filled blastocyst cavity), together surrounded by a trophectoderm-like tissue and the double layered cell aggregate has a diameter of about 10 µm to 200 µm (Column 15, Lines 8-14).
The instant Specification at Paragraphs [0085] and [0086] respectively, states:
In the blastoid, an inner tissue develops that resembles such epiblast and is referred to as epiblast-like tissue.
In the blastoid, an inner tissue develops that resembles such hypoblast and is referred to as hypoblast-like tissue.
As the prior art also forms blastoids, the blastoids would be expected to also show the characteristic inner tissue comprising epiblast-like and hypoblast-like tissue.
The teachings of Rivron et al. were discussed above.
The reference did not teach a method comprising human pluripotent stem cells
(hPSC) and trophoblast cells, or wherein the inhibitor of the Tgf pathway is a TGF-β inhibitor, as required by Claim 1;
or treating the aggregate with at least one candidate compound, as required by
Claim 9.
Babyatsky et al. teaches that the TGF family comprises TGF-α and TGF-β (Pg. 975, Abstract).
It would have been obvious to those of ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Rivron et al. of producing a mouse artificial blastoid/blastocyst (e.g. aggregate) comprising treating aggregated PSC with a modulator/inhibitor of the TGF pathway to use an inhibitor of the TGF-β pathway because there are only two pathways in the TGF family and the selection of either to inhibit would have been a matter of artisan preference. See the MPEP citing KSR at 2143, I., E. Those of ordinary skill in the art would have been motivated to make this modification in order to inhibit the action of a particular TGF cytokine during blastoid formation. There would have been a reasonable expectation of success in making this modification because the reference already discloses general modulation/inhibition of the TGF pathway and the art recognizes that the TGF family only has two pathways.
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 Rivron et al. of producing a mouse artificial blastoid/blastocyst (e.g. aggregate) comprising mouse embryonic stem (pluripotent) cells and trophoblast cells to use human embryonic (pluripotent) stem cells because the reference teaches that either source of cells may be used in the process. See the MPEP at 2144.06, II. Those of ordinary skill in the art would have been motivated to make this modification in order to assess the effect of candidate drugs on the artificial blastoid/blastocyst model. There would have been a reasonable expectation of success in making this modification because the reference teaches that the pluripotent stem cells and trophoblasts may be obtained from mice or humans.
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 Rivron et al. of producing an artificial blastoid/blastocyst (aggregate) to treat the blastoid/blastocyst with at least one candidate compound because the reference teaches the obtained blastoid bears high promise for identifying novel drug targets and enhances the probability of clinical success of new drugs. Those of ordinary skill in the art would have been motivated to make this modification in order to assess the effect of candidate drugs on the artificial blastoid/blastocyst model. There would have been a reasonable expectation of success in making this modification because the reference suggests the use of the artificial blastoid/blastocyst model in drug testing.
With regard to the limitation of Claim 9, "for testing or screening a candidate
compound and/or candidate genetic alteration on having an effect at blastoid formation
and/or implantation of a blastoid into a layer of endometrial cell", this amounts to
recitation of an intended use which does not result in a structural/manipulative
difference which patentably distinguishes between the claimed invention and the prior
art.
The Examiner notes that while the reference does not provide a single
anticipating embodiment of the claimed invention it does separately provide each
claimed element, the only difference being combination of all the elements into a single
process. See the MPEP at 2143, I., A., referencing KSR.
It would have been obvious to those of ordinary skill in the art to have combined those separately taught elements into a single process in order to produce an artificial blastoid/blastocyst. Those of ordinary skill in the art would have been motivated to make this modification in order to obtain the desired artificial blastoid/blastocyst. There would have been a reasonable expectation of success in making this modification because all the elements are separately taught in the Rivron et al. reference.
Claims 1-4, 5, 6, 7 and 9 are rejected under 35 U.S.C. § 103 as being unpatentable over Rivron et al. (US 9,822,336 B2), of record, in view of in view of Babyatsky et al. (1996), as applied to Claims 1-4, 6, 7 and 9 above, and further in view of Simmons (WO 2005/065666 A1).
The teachings of Rivron et al. and Babyatsky et al. were discussed above. As discussed above Rivron teaches any combination of modulation (activation or inhibition) is applied (Column 23, Lines 12-15)
Rivron et al. did not teach wherein the PKC inhibitor is Gö6983 or Ro-31-8425, as required by Claim 5.
Simmons teaches that Gö6983 and Ro-31-8425 are both known PKC inhibitors (Pg. 3, Paragraph [0011] and Pg. 4, Paragraph [0014]).
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 Rivron et al. of producing an artificial blastoid/blastocyst comprising seeded PSC which have been treated with an unspecified modulator/inhibitor of the PKC pathway to use one of the PKC inhibitors taught by Simmons because Rivron et al. generally teaches a PKC modulator/inhibitor and Simmons provides specific PKC inhibitors. Those of ordinary skill in the art would have been motivated to make this modification because the general method of Rivron et al. does not provide specific PKC inhibitors which would be suitable for the method. Thus, the ordinary artisan would look to the prior art for suitable PKC inhibitors. There would have been a reasonable expectation of success in making this modification because Rivron generally teaches PKC modulators (including activators/inhibitors) and Simmons teaches specific PKC inhibitors.
Claims 1-4 and 6-9 are rejected under 35 U.S.C. § 103 as being unpatentable over Rivron et al. (US 9,822,336 B2), of record, in view of Babyatsky et al. (1996), as applied to Claims 1-4, 6, 7 and 9 above, in view of Evans et al. (2019), of record.
The teachings of Rivron et al. were discussed above.
Rivron et al. did not teach a method further comprising the stimulation of endometrial cells with a compound selected from estrogen, estrone, estriol, ethinyl estradiol, 17a-ethyInylestradiol, mestranol, progesterone, a progestin, cAMP, and a Wnt-inhibitor, and the seeding of the seeding of the blastoid onto the layer of stimulated endometrial cells that allows the blastoid to attach and invade the layer of endometrial cells, as required by Claim 8.
Evans et al. teaches stimulation of a monolayer of endometrial cells with either estrogen or progestin before seeding with a Trophectoderm spheroid onto the monolayer allowing attachment and invasion of the monolayer (Pg. 8, Fig. 1e, f and Pg. 9, Column 2, Lines 6-23), wherein the model can be used to discriminate between endometrial epithelial cells obtained from "fertile" vs. "infertile" women and is a potential "diagnostic" tool of endometrial infertility (Pg. 5, Abstract).
It would have been obvious to those of ordinary skill in the art before the effective
filing date of the claimed invention to modify the method of Rivron et al. of producing an
artificial blastoid/blastocyst (aggregate) to combine the method with the method of
Evans et al. of applying a trophectoderm spheroid to endometrial cells and assessing
attachment and invasion of the monolayer because Rivron et al. provides a
blastoid/blastocyst model and Evans et al. provides an embryo/endometrial adhesion
model which requires a blastoid/blastocyst/trophectoderm spheroid. Those of ordinary skill in the art would have been motivated to make this modification in order to provide a diagnostic for endometrial infertility in a subject.
There would have been a reasonable expectation of success in making this modification because the Rivron reference provides an artificial embryo and Evan teaches a diagnostic method which requires an embryo.
Response to Arguments
Applicant’s arguments, see Remarks, filed 07/06/2026, with respect to the above withdrawn objections/rejections have been fully considered and are persuasive. The remaining arguments have been considered only insofar as they apply to the pending rejections.
The Applicant argues that the cited reference does not teach or suggest the limitations of amended Claim 1. Applicant notes that Rivron discloses the HIPPO pathway inhibitor as an inhibitor of maturation in an already formed blastoid and not during the initial stage (Remarks, Pg. 10, Lines 1-9).
This is not found to be persuasive for the following reasons, as discussed above Rivron et al. teaches a method comprising 3D culturing (in a non-adherent surface microwell) an aggregate of mouse embryonic stem (pluripotent) cells in a first culture medium, wherein the first culture medium comprises a modulator of the MAPK pathway, wherein MAPK is known as ERK (Column 20, Line 25 and MEK is also called ERK, see published application at Paragraph [0053]) and a modulator of the TGF and PKC pathways;
and then adding trophoblast cells and culturing in a second medium comprising a modulator of the HIPPO pathway (Column 38, Claims 1 and 5); wherein a blastocyst-like cell aggregate is generated (Abstract); and wherein the modulator of the HIPPO pathway may be an inhibitor, such as GPCR ligands (lysophosphatidic acid receptor is a GPCR), such as GPR30 ligands, such as estradiol and tamoxifen (Column 22, Lines 66-67 and Column 23, Lines 1-8). Thus, the reference teaches HIPPO inhibition in the initial stage of blastoid formation. The citation by Applicant merely states that pluripotency of the blastoid is maintained by modulating at least one of 5 possible pathways, of which HIPPO is one. Rivron et al. also specifically teaches that HIPPO inhibition is preferred for the formation of at least double layered cell aggregate (e.g. the initial stage of blastoid formation) (Column 22, Lines 66-67 and Column 23, Lines 1-3).
The Applicant argues that the disclosure by Rivron of MAPK activation makes it non-obvious to use an MAPK inhibitor (Remarks, Pg. 10, Lines 10-12).
This is not found to be persuasive for the following reasons, as discussed above, Rivron teaches the use of a modulator of the MAPK pathway and wherein any combination of modulation (activation or inhibition) is applied (Column 23, Lines 12-15). Thus, the reference generally discloses both activation and inhibition and while activation may be the preferred embodiment, inhibition is still taught by the reference and obviated.
The Applicant argues that the disclosed MEK inhibitor PD0325901 is routinely used in mESC culture but not for blastoid generation. Applicant notes that while Rivron mentions pathway “modulators”, including the MAPK/MEK pathway inhibitor PD0325901, an MEK inhibitor is not disclosed for blastoid generation (Remarks, Pg. 10, Lines 13-19 and Pg. 11, Lines 1-4).
This is not found to be persuasive for the following reasons, as discussed above, Rivron teaches the use of a modulator of the MAPK pathway during blastoid formation (Column 38, Claims 1 and 5) and wherein any combination of modulation (activation or inhibition) is applied (Column 23, Lines 12-15). Thus, the reference generally discloses both activation and inhibition and while activation may be the preferred embodiment, inhibition is still taught by the reference and obviated. Rivron et al. further teaches a method comprising 3D culturing an aggregate of mouse embryonic stem (pluripotent) cells in a first culture medium, wherein the first culture medium comprises a modulator of the MAPK pathway, wherein MAPK is known as ERK (Column 20, Line 25 and MEK is also called ERK, see published application at Paragraph [0053]). Thus, the ordinary artisan would recognize that an MAPK modulator is also a modulator/inhibitor of ERK/MEK. While the reference may disclose an embodiment wherein a particular MAPK/MEK pathway inhibitor PD0325901 is used during ES culturing, the teachings of the reference are not limited to the disclosed embodiments and the reference is still relevant for its’ broader teachings.
No claims are allowed.
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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