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 .
Response to Amendment
The Amendment filed 08/11/2025 has been entered. Applicant’s amendments are in response to in the Non-Final Office Action mailed 05/09/2025. Applicant’s claims have been amended in the following manner: independent claim 1 has been amended that importantly limits the polyamine molecular weight to less than 500 Daltons, but also removes simpler polyamines from the Markush grouping represented by the Table of compounds (thus, significantly narrowing the polyamine limitations), claim 3 further narrows the polyamine species, and new claim 11 (introducing amylose or cellulose species limitations) has been entered to prompt a new ground of rejection on the amended claim set.
The Examiner further acknowledges the following:
Claims 1 and 3-11 are pending.
Claims 5-10 are withdrawn from consideration as directed to non-elected inventions.
Claims 1, 3-4, and 11 are presented for examination and rejected as set forth below.
New 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, 3-4, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Uludag (US20110251265A1), and in further view of Pediaa (Difference Between Amylose and Cellulose, 2015), Xiao (Progress in Polymer Science, 2017), Shen (International Journal of Nanomedicine, 2017), and Domb (US20020146826A1), as evidenced by Zhong (J. Agric. Food Chem. 2006).
Applicant’s claims are directed to a polycationic polysaccharide, wherein the polycationic polysaccharide is obtained by a reaction between a polysaccharide and a polyamine. Claims 3-4 further narrow the structure of the polycationic polysaccharide.
Uludag teaches polyamine-containing polymers and methods of their synthesis and use as transfection agents (abstract, [0014]).
Regarding claims 1 and 3-4: Uludag teaches a polymer such as the polysaccharide dextran that is modified by one or more polyamine groups such as diethylenetriamine (the structure of instant compound 1 of instant claim 3) (Uludag – claims 1-4) via a carbamate linkage (Uludag – claim 19).
Uludag teaches the aminodextran derivative in Scheme 2, which follows from carbamate formation on dextran [0095]. Below is an image of an aminodextran derivative from Scheme 2 on pg 11 from Uludag:
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Uludag teaches that the effectiveness of hemicellulose and dextran support the hypothesis that any polysaccharide which can be modified in a polar organic solvent would work according to the invention [0141-0142], and that using different polysaccharides leads to different transfection efficiency [0141-0142].
In addition to the diethylenetriamine used above, Uludag teaches that polyamines can be described by the structure of Formula I (which are ethyleneimines that can be less than 500 Daltons), where N = 1-10 [0045], and that reagents based on branched ethyleneimines are advantageous such as tris(2-aminoethyl)amine used in sample 0429-4 ([0133], Table 2). Note that Uludag does not specifically teach against using higher molecular weight oligoamines to graft to the polysaccharide.
In summary, Uludag teaches the derivatization of polysaccharides with polyamines such as diethylenetriamine attached to carbamate to produce polycationic polysaccharides for use as transfection agents, and provides motivation to select different polysaccharides and branched ethyleneimines in the disclosure. However, Uludag does not teach the specific linear polysaccharides (instant claim 1), specific branched polyethyleneimine species (instant claims 1 and 3), the monosaccharide unit number of 2-2000 (instant claim 4), and amylose or cellulose (instant claim 11).
Pediaa teaches amylose as a linear polysaccharide polymer with number of units from 300 to several thousand for amylose and a 1-4 glycosidic linkage (second paragraph). The hydroxyls of the polymer are free to be modified in the same way as dextran, which is a requirement for modification according to Uludag.
Xiao teaches different O-glycosidic linkages, including alpha-(1 → 2)-, -(1 → 3)-, -(1 → 4)-, -(1 → 6)-, and beta-(1 → 2)-, -(1 → 3)-, -(1 → 4)-, and -(1 → 6)-linkage (Fig. 2) (Figure 2, pg 79, paragraph 2) and general methods of making (whole document).
Shen teaches polyethylenimines (PEI) as transfection reagents (abstract). Shen shows that branching of a linear polyethylenimine is an obvious variation to make (Figure 1, linear (D) vs. branched (B)). Furthermore, Shen teaches that branched PEIs are in the liquid state and water-soluble, whereas linear PEIs are solid at room temperature and less soluble in certain solvents.
Domb teaches cationic polysaccharide compositions for gene transfer [0069] where an oligoamine is grafted to a polysaccharide (of 2-2000 monosaccharide units [0036]) by a carbamate bond (Domb – claim 7), and the oligoamine formula is below, and there is no limit to the “n” value and inclusive of linear and branched oligoamines (Domb – claim 8, [0038, 0050-0054]), where the oligoamine (as linear, cyclic, or branched) molecular weight can be up to 2000 Daltons (i.e., approximately 46 ethyleneimine units, making obvious the polyamines of instant tables in claim 1 and 3) [0084], demonstrating a wider MW range compared to Uludag.
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It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Uludag by using amylose (taught by Pediaa) or other linear polysaccharides (taught by Xiao) as the polysaccharide because Uludag teaches that generally any polysaccharide which can be modified in a polar organic solvent is suitable for use in the invention for the purpose of transfection [0142], and amylose (for example) is a polysaccharide with monosaccharide units of 300 to several thousand (the structural similarity with dextran would suggest it is also soluble in polar organic solvents, and it is known to be soluble in highly polar DMSO, as evidenced by Zhong in Table 5 “amylopectin and amylose were heated and stirred in DMSO separately”) with available hydroxy groups that are available to be derivatized into polycationic polysaccharides for the same purpose. Furthermore, Xiao demonstrates methodology (entire review) to produce non-natural linear oligosaccharides with structures similar to linear amylose, bearing different glycosidic linkages. Thus, it would be prima facie obvious to construct linear polysaccharides based on the different glycosidic linkages taught by Xiao. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Finally, Uludag demonstrates the improved transfection efficiency of DETA-modified dextran compared to DETA-modified hemicellulose, demonstrating that trying new polysaccharides for improved transfection efficiency is something a person of ordinary skill in the art would attempt to optimize [0141-0142].
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to introduce additional branching into the linear ethylenimine polyamine formula taught by Uludag and use higher molecular weight polyamines because it is a known structure activity optimization strategy for PEIs as applied to transfection agents (including polysaccharide and polyamine conjugates) as taught by Shen and Domb, and Uludag’s invention is directed toward novel transfection agents. Uludag also states a desire for water soluble transfection agents with improved transfection efficiency and less toxicity [0008], and altering the branching of the PEI (Shen teaches branched PEIs shown different solubility properties) would be one route of optimization a person of ordinary skill in the art would attempt to improve solubility, improve transfection efficacy, and reduce toxicity. Uludag shows modulation of the amine group used for conjugation provides varying degrees of solubility and transfection efficiency (Table 2, [0133]) and furthermore, Uludag teaches that branched ethyleneimines can be advantageous in terms of transfection ability [0133], providing motivation to make other branched ethyleneimines to conjugate with polysaccharides, with branching strategies demonstrated in Shen and Domb. Finally, Domb teaches cationic polysaccharide compositions for gene transfer [0069], where the oligoamine (as linear, cyclic, or branched) molecular weight can be up to 2000 Daltons (i.e., approximately 46 ethyleneimine units) [0084]. Thus, these oligoamines are suitable grafting agents for polysaccharides to make gene transfer agents. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
Finally, the extension of Uludag’s teachings to other polysaccharides (as suggested by Uludag with additional polysaccharides demonstrated by Pediaa and Xiao) and other polyamines (where Uludag initially conducts SAR on simple linear and branched polyamines and Shen and Domb disclose more complex polyamines) of the instant claim is obvious due to the expected properties of the proposed final conjugates (as exemplified by the instant claim set) based on the simpler examples of Uludag. Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). This is especially expected because Uludag teaches a motivation for use of any linear or branched polysaccharide [0142] and polyethylenimine ([0045, 0133], Table 1-2), as suitable for making polysaccharide polyamine conjugate transfection agents (abstract). Thus, the instant polycationic polysaccharides are obvious based on the prior art that discusses linear polysaccharides (i.e., Uludag, Pediaa and Xiao) and polyamines (i.e., Uludag, Shen, and Domb), and the motivation found in Uludag to vary the polysaccharide and polyamine components to optimize transfection performance.
Response to Arguments
Applicants arguments, see pg 35-42, filed 08/11/2025, with respect to the 103 rejection of claims 1 and 3-4 under rejection have been fully considered but they are not persuasive. The 103 rejection has been modified with respect to amendments made to the claim set and new added claims.
On page 35-36, Applicant discusses claims status and minor modifications, which is noted.
On page 36-37, Applicant argues that the art fails to disclose the polyamine compounds of the amended claim 1 (and claim 3). The extension of Uludag’s teachings to more complex polysaccharides and polyamines (not explicitly discussed in Uludag) is obvious due to the expected properties of the proposed final conjugates (also discussed in the 103 above). Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). This is especially expected because Uludag teaches a motivation for use of any linear or branched polysaccharide [0142] and various polyamines ([0045, 0133], Table 1-2), as suitable for making polysaccharide polyamine conjugate transfection agents (abstract). Thus, the instant polycationic polysaccharides are obvious based on the prior art that discusses linear polysaccharides (i.e., Uludag, Pediaa, and Xiao) and polyamines (Uludag, Shen, and Domb).
On page 37-38, Applicant argues (firstly) that Shen discloses high molecular weight polyethyleneimines. However, Applicant correctly states Uludag discloses low molecular weight polyamines (< 500 Daltons, as recited by the instant claims). All elements of each prior art reference need not read on the claimed invention, rather, the proper test for obviousness is what the combined teachings would have suggested to a person of ordinary skill in the art. In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). Thus, it is obvious to apply Shen’s disclosure of making branched polyethyleneimines (pg 5444, figure 1) to make larger or branched polyethylenimine homologs (compared to Uludag’s disclosure), which are expected to exhibit similar properties (as discussed above in the language for homologs). Furthermore, as evidenced by Bieber (BioTechniques 2001), polyethyleneimines (PEIs), as discussed in the Art, are not limited to the molecular weight definition of Shen, where they can represent polymers from 200 Da to 800 kDa (pg 74, introduction). Finally, Domb teaches linear and branched oligoamines (Domb – claim 8, [0038, 0050-0054]), where the oligoamine (as linear, cyclic, or branched) molecular weight can be up to 2000 Daltons (i.e., approximately 46 ethyleneimine units) [0084], demonstrating a wider MW range compared to Uludag.
On page 38, Applicant argues (secondly) that a PHOSITA would not be motivated to use a branched polyamine instead of a linear polyamine, based on a technicality of the species discussed by Uludag for comparison. Note that Uludag states “the transfectionability of reagent 0429-4 is similar to that of 0429-1—suggesting that a branched ethyleneimine is advantageous” [0133], which is sufficient direct motivation to use branched ethyleneimines for a PHOSITA, reading Uludag’s disclosure. Furthermore, Domb teaches branch polyamines as suitable for grafting to polysaccharides to make transfection agents.
On page 38-39, Applicant argues (thirdly) that Uludag and Shen do not teach a branched polyamine reduces toxicity comparison to a linear polyamine. The Examiner does not rely on this line of reasoning. However, a PHOSITA would be motivated to optimize Uludag’s polysaccharide polyamines by branching the polyamine because Uludag teaches an advantage of efficacy [0133]. Further Uludag is interested in making less toxic transfection agents [0008] and Shen teaches: (1) “These active amino groups, especially the primary and secondary amines, provide numerous possibilities for structural modifications, which enable them to target the agents and attenuate the potential toxicity.” (2) “Though PEIs of these two topologies are quite different, they both possess active amino groups, and the over-positive-charged nitrogens are always linked to the toxicity of PEI.” (pg 5444), which teaches a PHOSITA that structural modification of polyamines structure (especially with respect to the numerous amine groups), as related to linear and branched formats, can lead to differences in toxicity.
Furthermore, there is the teaching of Domb (reference that was brought into the modified rejection due to the amendment to the claim set and on the basis of the arguments) who teaches linear and branched polyamines conjugated to polysaccharides [0050-0054] by carbamate bonds (Domb – claim 7), that expand on the more limited teachings of Uludag, with respect to the variety and type of polyamine, where the oligoamine (as linear, cyclic, or branched) molecular weight can be up to 2000 Daltons (i.e., approximately 46 ethyleneimine units) [0084].
On page 39-40, Applicant argues that the polyamine compounds 94-142 have more than 10 ethyleneimine units to sufficiently distinguish them from Uludag. While this argument was especially considered, note that Domb demonstrates linear and branched polyamines conjugated to polysaccharides by carbamate bonds (Domb – claim 7), where the oligoamine (as linear, cyclic, or branched) molecular weight can be up to 2000 Daltons (i.e., approximately 46 ethyleneimine units) [0084]. Furthermore, homologs of Uludag’s invention are expected to bear similar properties to Uludag, and unexpected results have not been presented to counteract the obviousness of the rejection. Thus, based on the combined teachings of Uludag, Domb, and Shen, the Examiner argues that many of the polyamine species of instant claims 1 and 3 would be prima facie obvious based on the combined art and retained functional properties afforded by extending units of polymerization in the amine moiety.
Finally, a note for the Applicant on unexpected results of a specified composition (although no argument has yet been presented to differentiate Applicant’s claimed polycationic polysaccharide from related compositions of the Art): To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). Note that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Consequently, we must determine whether the results obtained in the closest prior art and those set forth by Applicants are sufficiently different in kind, and not merely in degree, so as to be unexpected by a person of ordinary skill in the art at the time of invention. See Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (Unexpected results that are probative of nonobviousness are those that are "different in kind and not merely in degree from the results of the prior art") (citation omitted). Also, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).
On page 40-41, Applicant argues that amylose and cellulose are insoluble in water. However, Uludag’s criteria for employing a particular polysaccharide is the following: “These results support the hypothesis that any polysaccharide which can be modified in a polar organic solvent could yield a product with transfection activity” [0142]. Also, amylose is known to be soluble in highly polar DMSO, as evidenced by Zhong in Table 5 “amylopectin and amylose were heated and stirred in DMSO separately.” Thus, the solubility of a polysaccharide in water is immaterial to the obviousness rejection. Furthermore, a PHOSITA would find rationale to select amylose based on the general statement of Uludag above, because the selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Finally, in order to teach away from a proposed modification, the art must “criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). The art does not criticize, discredit, or otherwise discourage the modification proposed by the Examiner (i.e., selecting amylose for incorporation into Uludag’s invention). Lastly, the final solubility of a transfection agent would be based on the properties resulting from the combination of a polysaccharide and a polyamine component (and not on the polysaccharide alone). Thus, the solubility of amylose and cellulose can be significantly altered based on polyamine substitution.
On page 42, Applicant concludes.
Correspondence
Applicant's amendment necessitated the new ground 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 extension fee 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 date of this final action.
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/R.P./Examiner, Art Unit 1614 9/5/25
/ALI SOROUSH/Supervisory Patent Examiner, Art Unit 1614