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 .
Applicant canceled claims 4, 34-41 and 43.
In view of the amendment, all previous 112(b) and 112(d) rejections are hereby withdrawn.
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.
Claim Objections
Claims 29-32 are objected to because of the following informalities: on line 2 in each of the claims 29-32, applicant need to change “the thermoreversible polymer” to --- the thermoreversible, random copolymer --- (to provide a proper antecedent basis). Appropriate correction is required.
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 1-3 and 5-32 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.
In claim 1, the thermoreversible, random copolymer is represented by instant formula (I), and as shown from the formula, each of the co-monomer units comprises an acrylamide backbone. Yet, on lines 1 and 3 of claim 1, applicant recite that the thermoreversible, random copolymer comprises a N-lower alkyl amine group-containing co-monomer. However, such recitation is not consistent with the copolymer of instant formula (I) because the formula (I) does not contain an amine group, thus causing confusion.
Instant 112(b) rejection can be overcome by changing “a N-lower alkyl amine group-containing co-monomer;” to --- a N-alkylacrylamide co-monomer; --- (so as to be consistent with the monomer unit “b” of instant formula (I)). The Examiner would also like to recommend applicant to change “a poly(ethylene glycol) (PEG) group-containing co-monomer,” to --- a poly(ethylene glycol) (PEG) group-containing acrylamide co-monomer, --- (also to be consistent with instant formula (I)).
Claims 2-3 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.
(i) In claim 2, applicant recite “the lower alkyl amine co-monomer” on line 3. For the same reason explained in Paragraph 7 above, applicant need to change “the lower alkyl amine co-monomer” to --- the N-alkylacrylamide co-monomer --- on line 3.
(ii) Furthermore, on the last line of claim 2, applicant recite “the terminal PEG monomer is . . .”. Applicant need to change “the terminal PEG monomer is” to --- the terminal PEG monomer of the PEGn is --- (so as to make the meaning of the claim more clear).
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1-3 and 5-32 are rejected under 35 U.S.C. 103 as being unpatentable over Rodrigues et al (US 2018/0251730 A1) in view of Yao et al (CN 101580585 A and its English translation) and Schonhammer (EP 2 323 623 B1).
Rodrigues teaches (claim 3 and [0102]) a thermoreversible polymer comprising (i) a N-isopropylacrylamide co-monomer, (ii) an alkyl [meth]acryl[ate/amide] co-monomer (which refers to a co-monomer that is an alkyl acrylate, an alkyl methacrylate, an alkyl acrylamide or an alkyl methacrylamide) and (iii) a PEG acrylamide co-monomer. Based on such teaching, one skilled in the art would immediately envisage a thermoreversible polymer comprising (i) a N-isopropylacrylamide co-monomer, (ii) an alkyl acrylamide co-monomer and (iii) a PEG acrylamide co-monomer.
The N-isopropylacrylamide co-monomer in Rodrigues’s thermoreversible polymer teaches instant monomer unit “a” of instant formula (I) as well as instant monomer unit “a” of instant formula (II) of claim 12.
With respect to instant monomer unit “b” of instant formula (I), Rodrigues teaches ([0078]) that the “alkyl” group (as in its alkyl acrylamide co-monomer) refers to a monovalent saturated aliphatic hydrocarbyl group having 1-6 carbon atoms (instant lower alkyl group – see [0020] of present specification) , which specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and neopentyl. Based on such teaching, it would have been obvious to one skilled in the art to have Rodrigues’s alkyl acrylamide co-monomer to be n-butyl acrylamide co-monomer, which teaches instant monomer unit “b” of instant formula (I) as well as instant monomer unit “b” of instant formula (II) of claim 12) with a reasonable expectation of success.
With respect to instant monomer unit “c” of instant formula (I), Rodrigues teaches ([0103]) that its PEG acrylamide co-monomer refers to an N-alkyl acrylamide further substituted on the alkyl sidechain with a polyethylene glycol (PEG) or modified polyethylene glycol where the PEG polymeric group includes water-soluble repeat units of –(CH2-CH2-O)- or –(O-CH2-CH2)-, and the reference further teaches that the number of such water-soluble repeat units can be from 2 to 50. According to such teaching, the resulting PEG acrylamide co-monomer unit in Rodrigues’s thermoreversible polymer would have a chemical structure of -(CH2-CH2)c-C(=O)-NH-R-(PEG)n, with c being a molar fraction of the co-monomer, R being the alkyl group (of the N-alkyl acrylamide) on which the (PEG)n polymeric group is attached and n being the number (from 2 to 50) of the water-soluble repeat units of –(CH2-CH2-O)- or –(O-CH2-CH2)-. Since, as discussed above, Rodrigues teaches ([0078]) that “alkyl” refers to monovalent saturated aliphatic hydrocarbyl group of 1-6 carbon atoms, which specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl and neopentyl, it would have been obvious to one skilled in the art to have the alkyl group R (as in the chemical structure of -(CH2-CH2)c-C(=O)-NH-R-(PEG)n) to be an ethyl group with a reasonable expectation of success, and the resulting chemical structure would be -(CH2-CH2)c-C(=O)-NH-CH2CH2-PEGn, with n being 2-50. In such structure, the terminal PEG in the PEGn is not further substituted with instant R2 group as required in instant formula (I) (i.e., the hydroxyl group in the terminal PEG is not end-capped). However, as evidenced by Yao et al ([0018]) and Schonhammer ([0007]), it is well known in the art to end-cap polyethylene glycol by using inert groups, such as methoxy group, to seal the polyethylene glycol and obtain improved stability. It would have been obvious to one skilled in the art to end-cap the terminal PEG monomer of (PEG)n by using inert groups, such as methoxy group, so as to seal the (PEG)n and obtain improved stability (by preventing unwanted reactions resulting from the chemically active hydroxyl group of the terminal PEG monomer). After the end-capping with a methoxy group, Rodrigues’s PEG acrylamide co-monomer unit as discussed above would have the final chemical structure of -(CH2-CH2)c-C(=O)-NH-CH2CH2-(PEG)n-OCH3 (i.e., hydroxyl group of the terminal PEG in (PEG)n is substituted with methoxy group, the methoxy group teaching instant R2 (heteroalkyl) group of claim 1, instant alkoxy groups of claims 2-3 and instant R2 (alkoxy) groups of claims 8-10), and such chemical structure (after the end-capping with a methoxy group) teaches instant monomer unit “c” of instant formula (I) as well as instant monomer unit “c” of instant formula (II) of claim 12.
With respect to instant G1 and G2 of instant formula (I), Rodrigues teaches (see [0105], [0114], claims 4 and 12) that the G1 and G2 segments (as shown in its thermoresponsive polymer of formula (I)) are independently selected from a polymer segment, a terminal group, a linker or a linked modifying agent (such as a hyaluronic acid). Thus, Rodrigues teaches instant G1 and G2 segments.
Thus, Rodrigues in view of Yao and Schonhammer renders obvious instant claims 1-3, 5-10 and 12.
With respect to instant claim 11, as discussed above, Rodrigues in view of Yao and Schonhammer teaches instant monomer units a, b and c of instant formula (I). Rodrigues further teaches (see claims 8 and 4) that for its thermoresponsive polymer of formula (I), a>0.8; 0.1>b>0; and 0.2>c>0 (with Rodrigues’s monomer unit “c” corresponding to instant monomer unit “b” and Rodrigues’s monomer unit “b” corresponding to instant monomer unit “c”). Thus, instant ranges for instant monomers units a, b and c of instant formula (I) would be a>0.8; 0.2>b>0; and 0.1>c>0. Thus, Rodrigues in view of Yao and Schonhammer renders obvious instant claim 11.
With respect to instant claim 13, Rodrigues teaches (claim 21) that the PEG or PEGn has a Mw of from 2kDa to 100 kDa. Thus, Rodrigues in view of Yao and Schonhammer renders obvious instant claim 13.
With respect to instant claims 14-22, for the reasons already explained above, Rodrigues in view of Yao and Schonhammer teaches instant monomer units a, b and c and instant G1 and G2 segments (with instant R1 being n-butyl, instant R2 being methoxy and instant n being 2-50). As to instant monomer unit “d” of instant formula (III), Rodrigues teaches ([0104]-[0105]) that its thermoreversible polymer discussed above may further comprises a modifying acrylamide co-monomer (such as the monomer unit “d” as shown in its formula (I)) comprising a linked functional group and/or a linked modifying agent, i.e., a substituted N-alkyl acrylamide co-monomer, which is substituted with an optional linker (which teaches instant “L” moiety in the monomer unit “d” of instant formula (III)) terminated with a functional group and/or a linked modifying agent: Rodrigues further teaches ([0125] and [0115]) that the functional group can be thiol, alkyne, cyclooctyne, azide or maleimide (instant chemoselective functional group of claim 21) and that the linked modifying agent can be heparin, hyaluronic acid, specific binding member, peptide, nucleic acid, gelatin, fibronectin, collagen, laminin, bFGF, EGF, insulin, progesterone, glucose, thymosin beta-4, SHH, Noggin, Activin, TGFb3, FGF8, BDNF, GDNF, NT3, PDGF-AA or IGF-1 (instant modifying agent of claim 22). Thus, Rodrigues teaches instant monomer unit “d” of instant formula (III) of claim 14 (with instant L being a linker and instant Z2 being a modifying agent or a chemoselective functional group). Thus, Rodrigues in view of Yao and Schonhammer renders obvious instant claims 14-22.
With respect to instant claim 23, as already explained above, Rodrigues teaches instant a>0.8; 0.2>b>0; and 0.1>c>0. As to instant range for “d” (0.1>d>0), Rodrigues teaches ([0118]) that in some embodiments, the molar fraction for the monomer unit “d” of its formula (I) (shown in [0105]) is greater than 0 and less than 0.1, i.e., 0<d<0.1. Thus, Rodrigues in view of Yao and Schonhammer renders obvious instant claim 23.
With respect to instant claims 24-28, as discussed above, Rodrigues’s thermoresponsive polymer comprises instant G1 and G2 segments selected from a polymer segment, a terminal group, a linker or a linked modifying agent (see [0114], claims 4 and 12). It would be obvious to one skilled in the art to have Rodrigues’s thermoresponsive polymer to comprise instant G1 and G2 moieties that are linked modifying agents. Among examples for the modifying agent, Rodrigues teaches ([0115]) heparin, hyaluronic acid, specific binding member, peptide, nucleic acid, gelatin, fibronectin, collagen and laminin (all of which teach instant modifying agents of claims 24 and 25). Furthermore, as also discussed above, Rodrigues teaches ([0104], [0105], [0109], [0111], [0131]) that its modifying acrylamide co-monomer (such as the monomer unit “d” included in Rodrigues’s formula (I)) comprise a linked modifying agent (i.e., as the Z2 group in the monomer unit “d”), and among examples for the linked modifying agent (Z2 group), Rodrigues teaches (see [0140]) growth factors, such as EGF (epidermal growth factor), TGF (transforming growth factor), FGF (fibroblast growth factor, for example, FGF-8), PDGF (platelet-derived growth factor), IGF(insulin-like growth factor) and a bone morphogenetic protein (all of which teach instant polypeptides of claims 27 and 28). Thus, Rodrigues in view of Yao and Schonhammer renders obvious instant claims 24-28.
With respect to instant claims 29-32, Rodrigues teaches ([0063] and [0092]) that in some cases, its thermoresponsive polymer is liquid at 4oC (which is 30oC or less as recited in instant claim 31) and is a solid, semi-solid or gel at 37oC (which is 20oC or more as recited in instant claim 29). Thus, Rodrigues in view of Yao and Schonhammer renders obvious instant claims 29-32.
Response to Arguments
With respect to instant 103 rejection over Rodrigues in view of Yao and Schonhammer, applicant argue that a prima facie case of obviousness has not been established because the cited combination of references does not teach or suggest every feature of the Applicant's claimed invention, and one of ordinary skill in the art
would have no apparent reason to modify the teaching of the cited art in order to obtain the presently claimed invention.
Applicant first point to Rodrigues’s general polymer of Formula (I) as reproduced below:
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200
415
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334
446
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Applicant then point to Rodrigues’s Formula II in which X1 is -O-, R2 is methyl and Z1 is NH2 and argue that the claimed and used structure of Rodrigues is significantly different from the structure of presently claimed invention, which contains NH in position X1 of Rodrigues, H in position R2 of Rodrigues, and Z1 (corresponding to R2 in the presently claimed invention) does not include a primary amine. Applicant further argue that Rodrigues does not teach or suggest instant thermoreversible, random copolymer of formula (I) shown in claim 1. The Examiner disagrees. After giving a general teaching ([0102]) of its inventive thermoreversible polymer comprising (i) a N-isopropylacrylamide co-monomer, (ii) an alkyl [meth]acryl[ate/amide] co-monomer (which refers to a co-monomer that is an alkyl acrylate, an alkyl methacrylate, an alkyl acrylamide or an alkyl methacrylamide) and (iii) a PEG acrylamide co-monomer, Rodrigues clearly states ([0105]) that “in some embodiments” its thermoreversible polymer comprises a polymeric segment represented by the formula (I) and also states ([0131]) that “in some embodiments” its thermoreversible polymer comprises a polymeric segment represented by the formula (II) and that “in some embodiments”, the thermoreversible polymer is represented by formula (I) or (II). Thus, Rodrigues’s teaching is not confined only to the thermoreversible polymer of Formula II. Also, the Examiner already explained above in detail how Rodrigues’s teaching (see the first five paragraphs within Paragraph 10 above) renders obvious instant thermoreversible random copolymer of formula (I) of claim 1. Besides, 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). See MPEP 2123(II). Furthermore, "[t]he 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).
Applicant furthermore point to Rodrigues’s teaching that Z¹ (the terminal group
attached to PEG in monomer “b”), is an optional terminal functional group or linked modifying agent and point to Rodrigues’s particular teaching in [0103], which states “[a] modified PEG can include any convenient terminal modifications, such as an amine, a thiol or a carboxylic acid, e.g., capable of conjugation with a modifying agent of interest.” Applicant then argue that Rodrigues specifically teaches that the terminal modification on the PEG is a functional group capable of conjugation with a modifying agent and thus, one skilled in the art would have no apparent reason to modify Rodrigues’s teaching to replace the terminal functional group capable of conjugation with a modifying agent with an inert end-cap, such as a methoxy group, as asserted in the Office Action. Applicant argue that such modification of Rodrigues’s teaching would render Rodrigues’s invention unsatisfactory for its intended purpose and impermissibly change the principle of operation of the Rodrigues’s invention. The Examiner disagrees. In [0103], Rodrigues teaches that its PEG acrylamide co-monomer refers to an N-alkyl acrylamide further substituted on the alkyl sidechain with a PEG or modified PEG and that the modified PEG can include any convenient terminal modifications, such as substitution or modification with a linked functional group such as an amine, a thiol or a carboxylic acid, for example, capable of conjugation with a modifying agent of interest. This means that the N-alkyl acrylamide does not even have to be further substituted (on the alkyl sidechain) with a modified PEG (i.e., it can be substituted with an unmodified PEG as well). Even if the N-alkyl acrylamide were further substituted with a modified PEG, the modification or substitution does not have to be with a functional group (amine, thiol or carboxylic acid) capable of conjugation with a modifying agent of interest. Rodrigues clearly teaches that the modified PEG can include any convenient terminal modifications, including the modification with a linked functional group capable of conjugation with a modifying agent of interest. As already discussed above, it is well known in the art, as evidenced by Yao and Schonhammer, to end-cap PEG by using inert groups, such as methoxy group, to seal the polyethylene glycol and obtain improved stability. It would have been obvious to one skilled in the art to end-cap the terminal PEG monomer of (PEG)n by using inert groups, such as methoxy group, so as to seal the (PEG)n and obtain improved stability (by preventing unwanted reactions resulting from the chemically active hydroxyl group of the terminal PEG monomer). Thus, the Examiner disagrees with applicant’s argument that since Rodrigues specifically teaches that the terminal modification on the PEG is a functional group capable of conjugation with a modifying agent, one skilled in the art would have no reason to modify Rodrigues’s teaching to replace the terminal functional group capable of conjugation with a modifying agent with an inert end-cap, such as a methoxy group, and that such modification of Rodrigues’s teaching would render Rodrigues’s invention unsatisfactory for its intended purpose and impermissibly change the principle of operation of the Rodrigues’s invention. As discussed above, the modification with a linked functional group capable of conjugation with a modifying agent of interest is just an example taught by Rodrigues for “any convenient” terminal modifications for the modified PEG if the N-alkyl acrylamide were to be further substituted with a modified PEG.
Applicant further argue that the hydrogel structure described by Rodrigues is specifically used for the differentiation of certain neural cells (oligodendrocyte precursor cells), whereas present invention focuses on the development of a specific method to produce a precise set of compounds with the goal of achieving better synthesis control and reproducibility by reducing unwanted crosslinking, to increase the compatibility of these compounds with industrial applications. Applicant argue that although Yao and Schonhammer describe end-cap PEG modifications using inert groups to seal the PEG and obtain improved stability, present invention does not focus on improving stability through PEG modifications but rather on preventing unwanted crosslinking to the backbone in order to achieve better synthesis control and reproducibility. However, applicant’s such argument is not found to be persuasive because the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc., 424 F.3d 1293, 1323, 76 USPQ2d 1662, 1685 (Fed. Cir. 2005) ("One of ordinary skill in the art need not see the identical problem addressed in a prior art reference to be motivated to apply its teachings."). See MPEP 2144(IV). See also MPEP 2144(II): The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983). See also Dystar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick, 464 F.3d 1356, 1368, 80 USPQ2d 1641, 1651 (Fed. Cir. 2006) ("Indeed, we have repeatedly held that an implicit motivation to combine exists not only when a suggestion may be gleaned from the prior art as a whole, but when the ‘improvement’ is technology-independent and the combination of references results in a product or process that is more desirable, for example because it is stronger, cheaper, cleaner, faster, lighter, smaller, more durable, or more efficient. Because the desire to enhance commercial opportunities by improving a product or process is universal—and even common-sensical—we have held that there exists in these situations a motivation to combine prior art references even absent any hint of suggestion in the references themselves."). As already discussed above, Rodrigues clearly teaches that the modified PEG can include any convenient terminal modifications (including the modification with a linked functional group capable of conjugation with a modifying agent of interest). Since Yao and Schonhammer indicated that it is well-known to end-cap PEG by using inert groups, such as methoxy group, to seal the PEG and obtain improved stability, it would have been obvious to one skilled in the art to end-cap the terminal PEG monomer of (PEG)n in Rodrigues by using inert groups, such as methoxy group (instant R2 group), so as to seal the (PEG)n and obtain improved stability (by preventing unwanted reactions resulting from the chemically active hydroxyl group of the terminal PEG monomer) because as stated above, the reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem and the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, supra.
For the reasons stated above, instant 103 rejection over Rodrigues in view of Yao and Schonhammer still stands.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
August 30, 2026
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