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 .
Claim Status
Claims 1-2, 10-12 and 28-39 are pending.
Claim 12 is withdrawn.
Claims 1-2, 10-11 and 28-39 are under examination.
Withdrawn Claim Objections
The objections to claims 2 and 10 because of informalities as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Withdrawn Claim Rejections - 35 USC § 112 (b)
The rejection of claim 1-2, 10-11 and 28 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
Moot Claim Rejections - 35 USC § 112 (b)
The rejection of claim 6 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite as set forth in the previous office action is moot in view of the cancellation of this claim.
New Claim Rejections - 35 USC § 112 (b)
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 30-37 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.
Claims 30-31 and 36-37 each recite specific components which overlap with those recite in claim 1, upon which each of these claims ultimately depends. However, claims 30-31 and 34-37 do not refer back to those components, so it is unclear whether the components recited in claims 30-31 and 34-37 are encompassed by the broader recitations in claim 1, or whether they are additional components in the composition.
Each specific issue of each of claims 30-31 and 36-37 is discussed below.
Claims 30 and 31 recite LDN193189 which is a BMP inhibitor, SB431542 which is a TGF a TGFB/Activin-Nodal inhibitor, recombinant SHH which is an SHH protein, SAG which is a smoothened agonist, CHIR99021 which is a GSK3β inhibitor and Blebbistatin which is a Myosin II ATPase inhibitor. For each of these embodiments, it is unclear whether these refer to the BMP inhibitor, TGFB/Activin-Nodal inhibitor, SHH protein, smoothened agonist, a GSK3β inhibitor and a Myosin II ATPase inhibitor of claim 1, upon which claims 30 and 31 each depend, or whether they are additional components in the composition.
Claims 36-37 each recite SB431542 which is a TGF a TGFB/Activin-Nodal inhibitor, LDN193189 which is a BMP inhibitor, SHH which is an SHH protein, SAG which is a smoothened agonist, CHIR99021 which is a GSK3β inhibitor and Blebbistatin which is a Myosin II ATPase inhibitor. For each of these embodiments, it is unclear whether these refer to the BMP inhibitor, TGFB/Activin-Nodal inhibitor, SHH protein, smoothened agonist, a GSK3β inhibitor and a Myosin II ATPase inhibitor of claim 1, upon which claims 36 and 37 each depend, or whether they are additional components in the composition.
Claim 32 contains the trademark/trade names DMEM, Neurobasal, and X-VIVO.
Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe cell culture media components and, accordingly, the identification/description is indefinite.
Because the reagents was developed by the manufacturer at the time of the applicant’s invention under the trade names and as a result are proprietary, which means what constitutes as DMEM, Neurobasal, and X-VIVO can change, and these changes do not need to be disclosed by these companies to the public. Accordingly, the identification of the trade name is indefinite and the applicant is advised to employ a sequence, the SeqID, IUPAC name and/or CAS number for this agent.
By nature of their ultimate dependency on claim 32, claims 33-37 are also rejected because they does not clarify the issue.
Response to Arguments
Applicant’s arguments, filed 1st, July, 2026 have been fully considered but are not found persuasive.
Applicant argues “With respect to "DMEM," "Neurobasal," and "X-VIVO," these terms carry universally recognized meanings in the relevant technical field, and a person of ordinary skill in the art (POSA) would readily understand the specific components to which they refer. Specifically, DMEM is Dulbecco's Modified Eagle's Medium, a well-known basal cell culture medium; Neurobasal is a
well-known basal medium for culturing neuronal cells (neurons); and X-VIVO is a well-known serum-free medium for hematopoietic and immune cell culture. The use of these product names does not introduce any ambiguity or indefiniteness into the claims” (pg. 1-2).
In response, Applicant is directed to MPEP 2173.05(u) which states that if a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). See also Eli Lilly & Co. v. Apotex, Inc., 837 Fed. Appx. 780, 784-85, 2020 USPQ2d 11531 (Fed. Cir. 2020).
Regarding trademarks, Applicant is directed to MPEP 608.01(v) which defines a trademark as follows:
The term "trademark" includes any word, name, symbol, or device, or any combination thereof-
(1) used by a person, or
(2) which a person has a bona fide intention to use in commerce and applies to register on the principal register established by this chapter,
to identify and distinguish his or her goods, including a unique product, from those manufactured or sold by others and to indicate the source of the goods, even if that source is unknown.
In the instant case, because "DMEM," "Neurobasal," and "X-VIVO," are each listed as wordmarks on the trademark database, and they are “used in a claim as a limitation to identify or describe a particular material or product,” in accordance with the guidance of MPEP 2173.05(u) the terms render the claim indefinite.
Furthermore the Examiner notes that although the Trademark with the number 98618988 (DMEM) was abandoned, it still meets the definition of a trademark according to the MPEP because it is a term “which a person has a bona fide intention to use in commerce” “to identify and distinguish his or her goods.” Since the trademark Application was filed (i.e. “applies to register on the principal register” MPEP 608.01(v) above), it falls under the definition of a trademark, even if the Trademark Status is now Dead/Abandoned.
Accordingly, for the reasons stated above, the claims are still indefinite due to the presence of the trademark terms.
Withdrawn Claim Rejections – 35 USC § 102
The rejection of claims 1-2, 11 and 28 under 35 U.S.C. 102(a)(1) as being anticipated by McMahon et al. (US-2018/0051248-A1; henceforth McMahon) as set forth in the previous office action is withdrawn in view of Applicant’s amendments.
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.
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.
Claims 1-2, 10-12 and 28-39 are rejected under 35 U.S.C. 103 as being unpatentable McMahon et al. (US-2018/0051248-A1; henceforth McMahon).
Regarding claim 1, McMahon discloses a composition for maintaining or increasing the number of nerve cells in vitro (D5 Aggregate Formation Medium; Table 2 pg. 16; see also “transferring the cells to a spinner flask suspension culture to form aggregates in D5 DA Neuron Aggregate Formation Medium” para. [0149]; Example 1) which comprises
a BMP inhibitor (Dorsomorphin),
a SHH protein (C25II SHH),
a Smoothened agonist (Purmorphamine),
a GSK3β inhibitor (CHIR99021), and
a Myosin II ATPase inhibitor (Blebbistatin) (D5 Aggregate Formation Medium; Table 2 pg. 16).
Regarding claim 1, while McMahon teaches including a single SMAD signaling pathway inhibitor of Dorsomorphin which is a BMP inhibitor in the composition (D5 Aggregate Formation Medium; Table 2 pg. 16), McMahon teaches TGFβ/Activin-Nodal inhibitors as SMAD inhibitors (para. [0005, 0007, 0051, 0053, 0055, 0082, 0084-0088, 0090]), and McMahon teaches TGFβ/Activin-Nodal inhibitors (transforming growth factor (TGF) antagonists; para. [0089]) may be included in the differentiation medium, McMahon is silent to a specific embodiment comprising a BMP inhibitor, a TGFβ/Activin-Nodal inhibitor, a SHH protein, a Smoothened agonist, a GSK3β inhibitor and a Myosin II ATPase inhibitor.
Nevertheless, regarding claim 1, Applicant is directed to which MPEP 2144.06 indicates that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Therefore, regarding claim 1, in the instant case, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the composition of McMahon, which includes a SMAD inhibitor and combine the TGFβ/Activin-Nodal inhibitor of McMahon, which is also a SMAD inhibitor, in order to form a third composition to be used for the very same purpose. Regarding the reasonable expectation of success, McMahon evidences preparation of compositions that include SMAD inhibitors ((D5 Aggregate Formation Medium; Table 2 pg. 16).
Regarding the preamble of claim 1, McMahon discloses the medium is for Neuron Aggregate Formation (D5 Aggregate Formation Medium; Table 2 pg. 16; see also “transferring the cells to a spinner flask suspension culture to form aggregates in D5 DA Neuron Aggregate Formation Medium” para. [0149]; Example 1) and therefore the suggested medium is capable of meeting the intended use of maintaining or increasing the number of nerve cells in vitro.
Regarding the preamble of claim 1, the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). In the instant case, for the reasons set forth above, McMahon teaches and makes obvious all the structural limitations of structurally complete invention in the claim body for the reasons set forth above and therefore meets instant claims.
Regarding claim 2, further to the discussion of claim 1 above, as stated above (see claim 1 rejection above), McMahon teaches:
the Myosin II ATPase inhibitor is Blebbistatin;
the BMP inhibitor is Dorsomorphin;
(d) the SHH protein is C25II SHH which is a terminal-modified SHH;
(e) the Smoothend agonist is Purmorphamine
(f) the GSK3β inhibitor is CHIR99021)(D5 Aggregate Formation Medium; Table 2 pg. 16)
Regarding claim 10, further to the discussion of claim 1 above, McMahon teaches including DMEM/12, which is a basal culture medium ( D5 Aggregate Formation Medium; Table 2 pg. 16). The recites “for culturing a nerve cell” is an intended use and the DMEM of McMahon meets the structure of instant claims and is therefore capable of meeting this intended use.
Regarding claims 11 and 28, further to the discussion of claims 1 or 10 above, respectively, as stated above (see claims 1 and 10 rejection above), McMahon teaches and makes obvious the required claim components for the composition (claim 1), and the cell culture media (claim 10).
Regarding the preamble of “a kit” of claims 11 and 28, the preamble merely states the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, and therefore the preamble is not considered a limitation and is of no significance to claim construction (see MPEP 2111.02) See also Rowe v. Dror, 112 F.3d 473, 478, 42 USPQ2d 1550, 1553 (Fed. Cir. 1997) ("where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation"). In the instant case, as set forth above, McMahon teaches and suggests all the structural requirements of claims 11 and 28 and therefore the composition taught by McMahon is capable of meeting the intended use of “a kit” and meets instant claim limitations.
Regarding claim 29, further to the discussion of claim 1 above, as stated above (see claims 1-2 rejection above, McMahon teaches the SHH is a terminal-modified SHH that is SHH C25II (D5 Aggregate Formation Medium; Table 2 pg. 16).
Regarding claim 30, further to the discussion of claim 1 above, McMahon teaches the composition comprises
a BMP inhibitor of LDN193189 (para. [0005-0007, 0036, 0051-0052, 0062, 0082, 0154-0155, 0158-0159, 0163, 0173]; Tables 1, 3-4, 6 ; Examples 2-3, 13; claims 3-6);
a recombinant SHH of C25II SHH (para. [0007, 0060-0061, 0082]; Table 1; claims 31 and 33);
a Smoothened agonist of SAG (“a Smoothened agonist, such as SAG-1” para. [0061]);
a GSK3β inhibitor of CHIR99021 (para. [0006-0007, 0058-0059, 0062, 0082, 0153, 0156]; Tables 1-6; Example 2; claims 23-36);
and a Myosin II ATPase inhibitor of Blebbistatin (para. [0008, 0014, 0112]; Tables 1-6; claims 47-48)
(see also “D5 Aggregate Formation Medium”; Table 2 pg. 16).
Regarding claim 30, McMahon suggests and makes obvious the TGFβ/Activin-Nodal inhibitor above (see claim 1 rejection above). McMahon specifically teaches the TGFβ/Activin-Nodal inhibitor of SB431542 (para. [0005-0007, 0053, 0062, 0082, 0158-0159]; Table 1; Example 3; claim 8) and it would therefore be obvious to use SB431542 in the suggested composition for the reasons set forth above.
Regarding claim 31, further to the discussion of claim 1 above, McMahon teaches including
a BMP inhibitor of LDN193189 (para. [0005-0007, 0036, 0051-0052, 0062, 0082, 0154-0155, 0158-0159, 0163, 0173]; Tables 1, 3-4, 6 ; Examples 2-3, 13; claims 3-6);
a recombinant SHH of C25II SHH (para. [0007, 0060-0061, 0082]; Table 1; claims 31 and 33);
a Smoothened agonist of SAG (“a Smoothened agonist, such as SAG-1” para. [0061]);
a GSK3β inhibitor of CHIR99021 (para. [0006-0007, 0058-0059, 0062, 0082, 0153, 0156]; Tables 1-6; Example 2; claims 23-36);
and a Myosin II ATPase inhibitor of Blebbistatin (para. [0008, 0014, 0112]; Tables 1-6; claims 47-48)
(see also “D5 Aggregate Formation Medium”; Table 2 pg. 16).
Regarding claim 31, McMahon suggests and makes obvious the TGFβ/Activin-Nodal inhibitor above (see claim 1 rejection above). McMahon specifically teaches the TGFβ/Activin-Nodal inhibitor of SB431542 (para. [0005-0007, 0053, 0062, 0082, 0158-0159]; Table 1; Example 3; claim 8) and it would therefore be obvious to use SB431542 in the suggested composition for the reasons set forth above.
However, regarding claim 31, McMahon does not explicitly suggest a single specific combination “consisting of” LDN193189, SB431542, a recombinant SHH, SAG, CHIR99021 and Blebbistatin.
Nevertheless, regarding claim 31, one of ordinary skill would have not considered the specific combination inventive because each of the components is specifically taught by McMahon, and one of ordinary skill would have been able to combine the known prior art elements of the culture components to obtain the predicable result of a composition for culturing cells with no change in their individual function (see MPEP 2143 (I) Exemplary Rationale (A)).
Therefore, because the specific combination of culture media components in the composition is a simple combination of known prior art elements that arrives at a predictable result, the specific combination as claimed is not inventive.
Regarding claim 32, further to the discussion of claim 1 above, McMahon teaches including DMEM/12, which is a basal culture medium ( D5 Aggregate Formation Medium; Table 2 pg. 16). The recites “for culturing a nerve cell” is an intended use and the DMEM of McMahon meets the structure of instant claims and is therefore capable of meeting this intended use.
Regarding claim 33, further to the discussion of claims 1 and 32 above, McMahon teaches the basal medium is further supplemented with one or more serum-free substitutes (“The medium may contain or may not contain any alternatives to serum” and “knockout Serum Replacement (KSR) and Chemically- defined Lipid concentrated (Gibco )” para. [0092]; see also N2 para. [0088]) and glutamine (para. [0086, 0088]) or a stabilized di peptide of L-alanyl-L-glutamine (Glutamax; Tables 1-6).
Regarding claim 34 further to the discussion of claims 1 and 32-33 above, McMahon teaches the basal culture medium is further supplemented with a N2 supplement (para. [0088]) and a stabilized di peptide of Lalany1-L-glutamine (Glutamax; Tables 1-6).
Regarding claim 35, further to the discussion of claims 1 and 32 above, McMahon teaches the concentration of BMP inhibitor LDN-193189 1-1,000 nm (para. [0052]), which is equivalent to the range of 0.0001 to 1 µm and which overlaps with the claimed range of 0.05-1 μM (McMahon also teaches other ranges of specific BMP inhibitors that overlap with the claimed range in para. [0052]);
the concentration of Shh protein C25II of about 1 to 1,000 ng/ml (para. [0060-0061]) which overlaps with the claimed range of 50-200 ng/mL SHH protein;
the concentration of SHH protein, which can include a Smoothened agonist, of about 0.1 to 10 μM (para. [0061]) which overlaps with the claimed range of 0.5-3 μM;
the concentration of GSK3β inhibitor of from about 0.1 to about 10 μM of a GSK3β inhibitor (CHIR99021; para. [0058]) which overlaps with the claimed range of 0.5-1.0 μM;
and a concentration of myosin II inhibitor of about 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 to about 100 μM (para. [0112]) which overlaps with the claimed range of 5-20 μM and also includes the specific range of 5-20 μM as “any range derivable therein” (para. [0112]).
Regarding claim 35, McMahon suggests and makes obvious the TGFβ/Activin-Nodal inhibitor above (see claim 1 rejection above). McMahon specifically teaches the TGFβ/Activin-Nodal inhibitor concentration range of 0.1 to 100 μM) (para. [0052]) which overlaps with the claimed range of 5-20 μM and it would therefore be obvious to use the taught concentration range of TGFβ/Activin-Nodal inhibitor in the suggested composition for the reasons set forth above.
Regarding claim 36-37, further to the discussion of claims 1 and 32 above, McMahon teaches the BMP inhibitor LDN-193189 para. [0005-0007, 0036, 0051-0052, 0062, 0082, 0154-0155, 0158-0159, 0163, 0173]; Tables 1, 3-4, 6 ; Examples 2-3, 13; claims 3-6) and McMahon teaches the concentration of BMP inhibitor LDN-193189 1-1,000 nm (para. [0052]), which is equivalent to the range of 0.0001 to 1 µm and which overlaps with the claimed range of 50-500 nM (McMahon also teaches other ranges of specific BMP inhibitors that overlap with the claimed range in para. [0052]);
McMahon teaches the SHH protein is SHH (“Sonic Hedgehog (Shh)” para. [0060]) and the concentration of SHH protein of about 1 to 1,000 ng/ml (para. [0060-0061]) which overlaps with the claimed range of 50-150 ng/mL SHH;
The composition can include a Smoothened agonist of SAG (“a Smoothened agonist, such as SAG-1” para. [0061]) with a concentration of about 0.1 to 10 μM (para. [0061]) which overlaps with the claimed range of 1-3 μM;
a GSK3β inhibitor of CHIR99021 (para. [0006-0007, 0058-0059, 0062, 0082, 0153, 0156]; Tables 1-6; Example 2; claims 23-36) at a concentration of from about 0.1 to about 10 μM of a GSK3β inhibitor (CHIR99021; para. [0058]) which overlaps with the claimed range of 0.5-1.0 μM;
and a Myosin II ATPase inhibitor of Blebbistatin (para. [0008, 0014, 0112]; Tables 1-6; claims 47-48) at a concentration of about 0.02, 0.05, 0.1, 0.2, 0.5, 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50 to about 100 μM (para. [0112]) which overlaps with the claimed range of 5-15 μM and also includes the specific range of 5-15 μM as “any range derivable therein” (para. [0112]).
Regarding claims 35-37, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). It is routine procedure to optimize component amounts to arrive at an optimal product that is superior for its intended use, since it has been held where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See M.P.E.P. §2144.05. In the instant case, regarding claims 35-37, the ranges taught and suggested by McMahon overlap with the instantly claimed ranges and thereby make them obvious.
Additionally, regarding claims 35-37, Applicant is reminded that generally, differences in concentration will not support patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical (MPEP 2144.05 II). Moreover, at the time of the claimed invention, one of ordinary skill in the art would have been motivated by routine practice to optimize the concentrations of the media components in the culture media with a reasonable expectation for differentiating pluripotent cells (abstract).
Regarding claim 37, the taught ranges encompass the specific values claimed by Applicant of 10 μM SB431542, 100 nM LDN193189, 100 ng/mL SHH, 2 μM SAG, and 10 μM Blebbistatin and thereby make them obvious unless there is evidence indicating that such concentration is critical.
Regarding claims 38-39, further to the discussion of claim 1 above, these claim further limits the type of cells in the preamble of claim 1 to neural progenitor cells (instant claim 38) and midbrain dopamine progenitors (instant claim 39). As stated above (see claim 1 rejection above) McMahon teaches and makes obvious all the structural limitations of structurally complete invention in the claim body for the reasons set forth above and therefore meets instant claims (see MPEP 2111.02). Furthermore, it is noted that McMahon teaches the intended use of the medium for Neuron Aggregate Formation (D5 Aggregate Formation Medium; Table 2 pg. 16; see also “transferring the cells to a spinner flask suspension culture to form aggregates in D5 DA Neuron Aggregate Formation Medium” para. [0149]; Example 1) and therefore the suggested medium is capable of meeting the intended use of maintaining or increasing the number of neural progenitor cells in vitro. Furthermore, McMahon teaches an intended use of differentiating the into midbrain DA neurons) and therefore the suggested medium is capable of meeting the intended use of maintaining or increasing the number of midbrain dopamine progenitors in vitro.
Hence, the claimed invention as a whole was prima facie obvious.
Response to Arguments
Applicant’s arguments, filed 1st, July, 2026 have been fully considered but are not found persuasive.
Applicant argues that “the Examiner's rejection is based on impermissible hindsight” (pg. 3-5).
In response, Applicant is directed to MPEP 2145 (X)(A) which states that "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). In the instant case, because the each of the claimed elements is made obvious by the combination as set forth above, which takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made, the reconstruction is proper.
In response, as fully set forth above, in the grounds of rejection above, each element of the claims is specifically addressed. While Applicant has alleged impermissible hindsight, Applicant has not articulated why the reasons set forth in the rejection of record are insufficient. Applicant is directed to MPEP 2142 which states that 35 U.S.C. 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references. "To support the conclusion that the claimed invention is directed to obvious subject matter, either the references must expressly or impliedly suggest the claimed invention or the examiner must present a convincing line of reasoning as to why the artisan would have found the claimed invention to have been obvious in light of the teachings of the references." Ex parte Clapp, 227 USPQ 972, 973 (Bd. Pat. App. & Inter. 1985). The rejection of record above provides a convincing line of reasoning as to why the artisan would have found the claimed invention to have been obvious in light of the teachings of the references and therefore the preponderance of the evidence is that the combined teachings render the claimed invention obvious. It is noted that Applicant argues that “impermissible hindsight cannot be used to lead the teachings of McMahon to the present invention, because the teachings of McMahon teach away from the claimed composition, and there is no teaching, suggestion, or motivation for a POSA to arrive at the present invention” (pg. 4-5). Arguments drawn to motivation to make the combination and reasonable expectation of success are addressed below.
Applicant argues “ The entire focus and inventive concept of McMahon is the use of mono-SMAD inhibition to generate midbrain dopaminergic (mDA) neurons. The abstract of McMahon states the invention is directed to "methods for differentiating pluripotent cells into midbrain dopaminergic (DA) neurons using a mono-SMAD inhibition." McMahon highlights the desirability and challenges of using only a single SMAD inhibitor, identifying it as a primary goal of the invention (see McMahon at para [0005]). McMahon explicitly characterizes prior art methods that use two inhibitors (dual-SMAD inhibition) as a limitation that the present invention overcomes” (pg. 3).
Applicant argues “To combine a BMP inhibitor (which McMahon teaches) with a TGFβActivin-Nodal inhibitor (as in claim 1 of the present application) is to abandon the core inventive principle of McMahon. It would be antithetical to the very purpose of McMahon's disclosure. The prior art teaches away from the claimed composition by presenting mono-SMAD inhibition as the superior and desired pathway. A POSA would not be motivated to disregard McMahon's central teaching to achieve success with a single inhibitor by adding a second inhibitor, especially when the entirety of McMahon is devoted to showing how to succeed without it” (pg. 3).
Applicant argues “the combination of a BMP inhibitor with a TGFβ/Activin-Nodal inhibitor does not flow logically. McMahon teaches these two classes of inhibitors as alternatives for the purpose of SMAD inhibition, not as complementary components. In fact, the examples in McMahon (e.g., Tables 3 and 4 and the "Condition 9" protocol) successfully generate mDA neurons using a single BMP inhibitor, such as LDN-193189 or Dorsomorphin, without a TGF β/ Activin-Nodal inhibitor. There is no suggestion, teaching, or motivation to combine the two; they are presented as different options to achieve the same singular goal of "mono-SMAD inhibition." (pg. 3-4).
In sum, Applicant argues that for the reasons stated above, that there is not motivation to make the combination (pg. 3-4) and that McMahon teaches away from the claimed invention (pg. 3-4).
In response to Applicant’s arguments that there is no motivation, as set forth above, the preponderance of the evidence is that because MPEP 2144.06 indicates that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980), it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the composition of McMahon, which includes a SMAD inhibitor and combine the TGFβ/Activin-Nodal inhibitor of McMahon, which is also a SMAD inhibitor, in order to form a third composition to be used for the very same purpose.
While Applicant argues “There is no suggestion, teaching, or motivation to combine the two,” an express “teaching, suggestion, or motivation” (MPEP 2143 (I) Exemplary Rationale (G)) is one possible rationale to support a conclusion of obviousness that is not relied upon by the Examiner above. The Examiner relies on the motivation of In re Kerkhoven that “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose (see MPEP 2144.06). Applicant is directed to MPEP 2143 which sets forth exemplary rationale for a finding of obviousness. MPEP 2143 states an explicit analysis does not require record evidence of an explicit teaching of a motivation to combine in the prior art. Furthermore, the exemplary rationales set forth in MPEP 2143 are not exhaustive. Specifically, the MPEP 2143 states that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel. Any rationale employed must provide a link between the factual findings and the legal conclusion of obviousness. (MPEP 2143 (I)).
In response to Applicant’s arguments above that McMahon teaches away, these are not found persuasive for the reasons stated below. While the disclosure of McMahon is directed to mono-SMAD inhibition (a single SMAD inhibitor), McMahon specifically teaches dual SMAD inhibition as known in the art and “typical” (see “methodologies for generating midbrain DA neurons from pluripotent cells typically require use of both LDN-193189, an inhibitor of BMP signaling (inhibits ALK 1/2/3/6, blocks SMAD 1/5/8), and SB-431542, an inhibitor of TGF-beta signaling (inhibits ALK 4/5/7, blocks SMAD 2/3), as described, e.g., in WO2013/067362. Since these methods utilize the combination of two inhibitors of Small Mothers Against Decapetaplegic (SMAD) signaling, these methods are typically referred to as "dual SMAD inhibition", or "dual SMADi"; para. [0005]) and McMahon shows Examples and data from dual SMAD protocols as controls or comparisons (see “optimized dual-SMADi protocol” para. [0032]; see also para. [0153-0155, 0158, 0165]; Examples 1-3). Although McMahon teaches a preferred embodiment of mono-SMAD, As stated above the prior art of McMahon clearly teaches dual SDMAS (two SMAD inhibitors) as a known alternative. Applicant is directed MPEP 2123 (II) which states that Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994).
Applicant is directed to MPEP 2145 which states that "the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) ("a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.") (internal quotations omitted) (quoting DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009)). In the instant case, because McMahon teaches dual-SMAD as a known and effective alternative to mono-SMAD, it does not teach away merely because it expresses a preference for mono-SMAD inhibition.
Applicant argues “As the Examiner acknowledges, McMahon is "silent to a specific embodiment comprising a BMP inhibitor, a TGFβ/Activin-Nodal inhibitor, a SHH protein, a Smoothened agonist, a GSK3β inhibitor and a Myosin II ATPase inhibitor" (Office Action, page 11). The fact that the combination is not taught, coupled with the fact that the goal of McMahon is to specifically avoid such a combination, makes it unpredictable. Adding a TGFβ/Activin-Nodal inhibitor to the established McMahon protocol would require the POSA to abandon the successful, validated mono-SMAD approach; undertake a new, untested differentiation strategy; and risk disrupting the delicate balance of signaling pathways required for efficient floor plate induction and dopaminergic specification. The complexity of the signaling networks makes the outcome of such a change unpredictable” (pg. 4).
Applicant argues “The Examiner cites McMahon's evidence of preparation of compositions that include SMAD inhibitors to support a reasonable expectation of success. This is insufficient. Showing that a single SMAD inhibitor works does not provide a reasonable expectation that two SMAD inhibitors, used concurrently, will work effectively, or that the specific combination of inhibitors recited in present claim 1 will work for the intended purpose. Success in one protocol does not guarantee success in a different, more complex, and contradictory protocol” (pg. 4).
In response, Applicant is reminded that conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). In the instant case, regarding reasonable expectation of success, McMahon specifically evidences preparations of compositions comprising that include SMAD inhibitors as well as the claimed components of a SHH protein, a Smoothened agonist, a GSK3B inhibitor, and a Myosin II ATPase inhibitor ((D5 Aggregate Formation Medium; Table 2 pg. 16) and therefore one of ordinary skill would have a reasonable expectation of success in preparing the suggested composition.
Further in response, this is not found persuasive because the claims are drawn to a composition with an intended use and not to a protocol and therefore a reasonable expectation of success is required to prepare the composition as suggested. As stated above, absolute predictability is not required. Applicant is directed to MPEP 2143.02 which states that where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016). In other words, while the prior art suggests the reason for modification, it is the preparation of the modification that requires a reasonable expectation of success. Achievement of the desired result, is not necessarily required. In the instant case, as set forth above, McMahon specifically evidences preparations of compositions comprising that include SMAD inhibitors as well as the claimed components of a SHH protein, a Smoothened agonist, a GSK3B inhibitor, and a Myosin II ATPase inhibitor ((D5 Aggregate Formation Medium; Table 2 pg. 16) and therefore one of ordinary skill would have a reasonable expectation of success in preparing the suggested composition. Although the intended use of the composition if for neuron cell culture (see McMahon abstract), this is an intended use as discussed above and it is not a structural requirement of the product of instant claims and therefore the reasonable expectation of success if met by the evidence of McMahon above that one of ordinary skill could prepare the structural requirements of the composition, and evidence of a reasonable expectation of success of the composition for use in a specific protocol to achieve specific results is not required in the instant case.
Furthermore, it is noted that even though a reasonable expectation of success in a culturing protocol is not required for the reasons stated above, McMahon specifically evidences that including two SMAD inhibitors, is known in the art and is known to result in generation of midbrain DA neurons from pluripotent cells (see “methodologies for generating midbrain DA neurons from pluripotent cells typically require use of both LDN-193189, an inhibitor of BMP signaling (inhibits ALK 1/2/3/6, blocks SMAD 1/5/8), and SB-431542, an inhibitor of TGF-beta signaling (inhibits ALK 4/5/7, blocks SMAD 2/3), as described, e.g., in WO2013/067362. Since these methods utilize the combination of two inhibitors of Small Mothers Against Decapetaplegic (SMAD) signaling, these methods are typically referred to as "dual SMAD inhibition", or "dual SMADi” para. [0005]).
Applicant argues “the claimed invention achieves unexpected advantageous effects” (pg. 4-5). Specifically, Applicant argues “According to the floor plate cell expansion experiment, in the floor plate cell expansion medium 2 (falling within the scope of present claim 1 ), the floor plate cells could be expanded for 50,000 times after 10 passages of expansion, and the immunofluorescence staining showed that the cells still stably expressed the floor plate cell markers FOXA2 and LMX1A (Figures 4, 5 and 6 of the originally filed specification). In the meantime, the expanded floor plate cells could be cryopreserved and stably differentiated into dopamine progenitor cells. The claimed composition can be used to stably produce high quality midbrain floor plate cells. It presents a solution specifically for the stable bulk expansion required in the production of intermediate cells for midbrain dopaminergic nerve cells. The effects exceed the reasonable expectations in the field even in view of McMahon, who is totally silent on the expansion of floor plate cells, and is unexpected” (pg. 4-5).
In response to Applicant’s arguments, this is not found persuasive for several reasons stated below.
In response to Applicant’s arguments, arguments of counsel cannot take the place of
factually supported objective evidence in the record. See In re Schulze, 346 F.2d 500, 602, 145
USPQ 716, 718 (CCPA 1965), In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed.
Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Thus,
Attorney statements regarding the unexpected result are not evidence without a supporting declaration. Specifically, Applicant has not provided objective scientific evidence on the record that the alleged unexpected results are facilitated over prior art products.
Concerning the alleged unexpected results, the burden is on the Applicant to establish results are unexpected and significant (MPEP 716.02(b)(I)), Applicants have the burden of explaining the proferred data (and MPEP 716.02(b)(II)), and the objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support (MPEP 716.02(d)(I)).
The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c) (MPEP 716.02(b)(I)). Evidence of unexpected properties may be in the form of a direct or indirect comparison of the claimed invention with the closest prior art which is commensurate in scope with the claims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP § 716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294, 298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433 (CCPA 1971) for examples of cases where indirect comparative testing was found sufficient to rebut a prima facie case of obviousness. (MPEP 716.02(b)(II)).
In the instant case, Applicant’s alleged unexpected results are insufficient to overcome the rejection of record under 35 U.S.C. 103 for several reasons. First, as discussed above, the alleged unexpected results are not supported by factually objective evidence on the record. While Applicant cites data in the specification, Applicant does not make a comparison to the closest prior art (see MPEP 716.02(b)). Specifically, the difference between the closest prior art and the instant claims is including both a BMP inhibitor and a TGFB/Activin-Nodal inhibitor and therefore evidence of alleged unexpected results would need to show that the closest prior art composition does not possess the allegedly unexpected properties. Because the data cited by Applicant is not compared to the closest prior art, the statistical and practical significance of the data (required by MPEP 716.02(b)(II); see above) are not apparent. Finally, it is not apparent whether the scope of the alleged unexpected results is commensurate in scope with the claimed invention. Figures 4, 5 and 6 cited by Applicant are labeled as floor plate cell expansion medium 1 (para. [00095] for figure 4 and floor plate cell expansion medium 2 for figures 5-6 (para. [00097]). From para. [000106], the Expansion mediums require the following specific concentrations of the following specific components, while instant claims are broader and do not require a specific BMP inhibitor, a TGFB/Activin-Nodal inhibitor, a SHH protein, a Smoothened agonist, or a specific a GSK3B inhibitor and also do not require specific concentrations.
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Claim Rejections - 35 USC § 103
Claims 11 and 28 remain rejected under 35 U.S.C. 103 as being unpatentable McMahon et al. (US-2018/0051248-A1; henceforth McMahon) as applied to claim 1 above, in view of Ahern (The Scientist Magazine, 1995 Archive accessed at https://www.the-scientist.com/technology/biochemical-reagents-kits-offer-scientists-good-return-on-investment-58425).
The teachings of McMahon above are hereby incorporated in their entirety.
Regarding claims 11 and 28, further to the discussion of claims 1 or 10 above, respectively,
McMahon does not teach a kit comprising the compositions.
Nevertheless, regarding claims 11 and 28, Ahern teaches preparing Kits to allow the product to be readily used in research by other scientists to accelerate the research process and allow them to spend more time on their primary research focus, rather than preparing reagents (pg. 3-5).
Therefore, regarding claims 11 and 28, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to prepare the compositions suggested by McMahon, and make them into a kit as suggested by Ahern to obtain the predictable result of a kit will cell culture components with a reasonable expectation of success. One of ordinary skill would have been motivated to do so as taught by Ahern because making the compositions into a kit would allow the product to be readily used in research by other scientists to accelerate the research process and allow them to spend more time on their primary research focus, rather than preparing reagents, as taught by Ahern (pg. 3-5). Regarding the reasonable expectation of success, Ahern evidences Kits (pg. 3-4).
Hence, the claimed invention as a whole was prima facie obvious.
Conclusion
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.
No claim is allowable.
Correspondence
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/BRIANA N EBBINGHAUS/Examiner, Art Unit 1632
/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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