DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on February 20 2026 has been entered.
Receipt of Arguments/Remarks filed on February 20 2026 is acknowledged. Claims 1-20, 24-31, 34-35 and 40 were/stand cancelled. Claim 41 was added. Claims 21-23, 32-33, 36-39 and 41 are pending. Claims 33 and 36-39 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on December 18 2024. Claim 21-23, 32 and 41 are directed to the elected invention.
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 Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 21-23 and 32 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Desai et al. (WO 2011088229, cited on PTO Form 1449) as evidenced by Steudle (Biophys J., 2011, cited in the Office action mailed on January 16 2025) and in view of Schwendeman et al. (US 20080182909).
Applicant Claims
The instant application claims a porous self-healing biodegradable polymer matrix suitable for encapsulation of an active macromolecule selected from the net positively charged peptides and net positively charged proteins, wherein the matrix comprises a biodegradable polymer and has pores and wherein: a biopolymer is disposed within the pores; and a pH modifying species is disposed within the pores; wherein the biopolymer comprises dextran sulfate and is present at a level of greater than 0.5% and below 10% by weight based on the weight of the biodegradable polymer, and wherein the pH modifying species comprises Mg(OH)2 and is present at a level of 1% to 7% by weight based on the weight of the biodegradable polymer.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Desai et al. is directed to active self-healing biomaterial system. Taught are methods and compositions that load and encapsulate an agent, such as a protein in a porous self-healing polymer. A delivery system includes a porous self-healing polymer, an ionic affinity trap within the pores of the self-healing polymer (claims 1, 3-5) and an agent associated with the ionic affinity trap (abstract and claims). Taught is a delivery system including a porous self-healing polymer, optionally a differentially soluble material such as a saccharide or disaccharide, and one or more ionic affinity traps and plasticizers. The differentially soluble material can be employed to obtain a porous self-healing polymer network and/or to stabilize the polymeric material. A self-healing polymer having a porous network, such as PLGA microspheres, can be prepared using established methods (paragraph 0090) In some embodiment the encapsulation efficiency is greater than 50% and, in some embodiments, greater than 99% with greater than 60, 70, 80, 90 and 95% also taught (paragraph 00104). Ionic affinity trap include zinc carbonate (ZnCO3) (paragraph 0034). Claimed ionic affinity traps include aluminum hydroxide, magnesium carbonate, etc. (claim 12). Other examples of ionic affinity traps include extracellular matrix-like materials include dextran sulfate, chitosan and hyaluronic acids (paragraph 00120). A differentially soluble material, such as a saccharide or similar material, can be used in forming the pores in the self-healing polymeric material. Useful saccharides include disaccharides such as sucrose and polysaccharides such as dextran and glycosaminoglycans such heparin. The saccharide can be used to stabilize an ionomer gel used as the ionic affinity trap (paragraph 00105). Exemplified amount of calcium phosphate (ionic affinity trap) is 3.4% (paragraph 00133) and aluminum hydroxide (i.e. alhydrogel, ionic affinity trap) is 2.3% (paragraph 00133) or 1.35% (paragraph 00130), 2.9% (paragraph 00131). Taught is sorbing an agent to an ionic affinity trap wherein a solid polymer matrix comprises the ionic affinity trap and an aqueous solution comprising the agent (claim 20). At least 90% of the agent in the sorbing step is sorbed to the ionic affinity trap (claim 39).Other examples include lysozyme encapsulated in PLGA containing 0, 1.5, 4.3 or 11% magnesium carbonate (paragraph 0071).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.012)
While Desai et al. teaches ionic affinity traps such as metals and extracellular matrix-like materials, Desai et al. does not expressly teach the use of both in the pores of the self-healing polymer network.
While Desai et al. exemplifies zinc carbonate as an ionic affinity trap, Desai et al. does not generally teach magnesium hydroxide. However, this deficiency is cured by Schwendeman et al.
Schwendeman et al. is directed to method for stabilizing biologically active agents encapsulated in biodegradable controlled-release polymer. Taught are preparing PLGA delivery systems which stabilize the soluble biologically active agents that are encapsulated therein (paragraph 0009). Stabilizing is achieved by providing a delivery system whose microclimate, i.e. the pores where the active agent resides, uniformly or homogeneously maintain a pH of greater than 3 and less than 8 (paragraph 0011). Basic additives include magnesium carbonate, magnesium hydroxide, zinc carbonate, aluminum hydroxide, etc. (paragraph 0013, table 1). The incorporation of the basic additive stabilizes therapeutic proteins (paragraph 0019). Example 3 studies the effect of zinc carbonate and calcium phosphate and calcium hydroxide on protein stability in PLGA millicylinders. It is taught that it may be desirable to add other excipients, such as sucrose to the delivery systems which contain high levels of salts in order to increase release duration (paragraph 0047).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Desai et and Schwendeman et al. and utilize ionomers such as magnesium hydroxide in combination with polysaccharides such as dextran sulfate. Desai et al. recognizes that hydroxide compounds can serve as the ionic affinity trap. Schwendeman et al. teaches that zinc carbonate, magnesium hydroxide and magnesium carbonate can stabilize the biologically active agents and suggests other excipients such as saccharides can increase release duration. As a general principle 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, the idea of combining them flows logically from their having been individually taught in the prior art. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) MPEP 2144.06. Thus, one of ordinary skill in the art would have a reasonable expectation of success in utilizing PLGA microspheres (self-healing biodegradable polymer matrix having pores) with a negatively charged polysaccharide such dextran sulfate in the pores as well as an ionic affinity trap/basic additive such as magnesium hydroxide in the pores, based on the teachings of Desai et al. and Schwendeman et al., in order to stabilize the active molecules and polymer as well as increase release duration. One skilled in the art would have a reasonable expectation of success as Desai et al. teaches an ionic affinity trap and Schwendeman et al. teaches basic additives which overlap in scope with the ionic affinity traps. Since both materials (basic additives and ionic affinity traps) are taught as stabilizers, there is a reasonable expectation of success in their use. Thereby rendering obvious instant claims 21-23.
Regarding the claimed amount of biopolymer in claim 21, Desai et al. teaches dextran-FITC in an amount of 65 mg/ml (6.5%) (paragraph 0060) which would read on the instant claims. However, Desai et al. does not expressly teach a range for the affinity trap. While the exact concentration is not disclosed by Desai et al., it is generally noted that differences in concentration do not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454,456, 105 USPQ 233, 235 (CCPA 1955). Given that applicant did not point out the criticality of concentration of the biopolymer of the invention, it is concluded that the normal desire of scientists or artisans to improve upon what is already generally known would provide the motivation to determine where in a disclosed set of ranges is the optimum concentration. Desai et al. teaches the ionic affinity trap serves to sorb the active agent. Thus, depending on the amount of active agent needed to be sorbed by the ionic affinity trap, one skilled in the art would manipulate the amount of ionic affinity trap.
Regarding claim 33, Desai et al. teaches encapsulation of active and specifically teaches lysozyme with PLGA. As evidenced by Steudle et al., lysozyme is a protein (i.e. peptide) which is positively charged (page 3017, protein models).
Response to Arguments
Applicants’ arguments filed February 20 2026 have been fully considered but they are not persuasive.
Applicants argue that (1) the prior art when taken alone or in combination fails to teach or suggest the specific combination of dextran sulfate and Mg(OH)2. It is argued that Desai teaches ionic affinity traps to sorb an agent in the present delivery system include bases such as metal salts and metal hydroxides and specifies aluminum hydroxide and aluminum phosphate are two ionic affinity traps that are particularly useful. In contrast to the repeated reference to metal salts and metal hydroxides, Desai mentions in passing on one occasion other examples of ionic affinity traps include dextran sulfate. Dextran sulfate as merely one or numerous possible ionic affinity trap options.
Regarding Applicants’ first argument, while Desai does teach metal salts and metal hydroxides as ionic affinity traps, Desai does teach dextran sulfate as a suitable ionic affinity trap. The MPEP (2143) makes it clear that examples of basic requirements of a prima facie case of obviousness is simple substitution of one known element for another to obtain predictable results. Desai clearly teaches that dextran sulfate is an ionic affinity trap, thus substitution of this particular ionic affinity trap for those expressly taught amounts to simple substitution of one known element for another. Thus, absent a demonstration of an unexpected effect, it is the examiners position that one skilled in the art would have utilized any of the taught ionic affinity traps with a reasonable expectation of success as they are all taught for the same purpose. This is further supported in MPEP 2144.06, as Desai teaches that dextran sulfate can serve as an ionic affinity trap. Thus, when forming porous polymer matrix with an ionic affinity trap, one would have used any known ionic affinity trap
Applicants argue that (2) Schwendeman ‘909 does not teach or suggest combining Mg(OH)2 with dextran sulfate. Schwendeman ‘909 teaches a variety of suitable basic additives. The Office Action relies on the principle that it is prima facie to combine compositions taught by the prior art to be useful for the same purpose. Applicants argue that this principle does not apply here as Desai teaches using ionic species for enhancing sorbing of an active agent and that in general proteins seem to better adsorb to the oppositely charged salts through simple electrostatic effects whereas Schwendeman ‘909 teaches using poorly soluble, mildly strong basic additives to stabilize the acidic microclimate. Stabilizing the degradation of PLGA and enhancing sorbing of an agent are not the same purposes and thus this reasoning cannot be used to support the claim rejections.
Regarding Applicants’ second argument, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Therefore, in order to render the claims obvious it is not necessarily that a single reference teaches all the claimed elements, it is what the combined teachings of the reference suggest. While Desai teaches using ionic affinity traps for sorbing of an active agent, Desai teaches the ionic affinity traps such as MgCO3 are stabilizer (see paragraph 0020; 0070). Taught by Desai is a porous self-healing polymer, optionally a differentially soluble material such as a saccharide or disaccharide, and one or more ionic affinity traps and plasticizers. The differentially soluble material can be employed to obtain a porous self-healing polymer network and/or to stabilize the polymeric material (paragraph 0090) wherein dextran is taught as a differentially soluble material (paragraph 00105). As a response to Applicants arguments that the prior art does not suggest the combination of MgOH2 and dextran sulfate, while this is specific combination is not expressly taught, paragraph 0090 of Desai clearly suggests the combination of a saccharide (which could be a polysaccharide such as dextran) and an ionic affinity trap. Additionally, Desai clearly teaches the ionic affinity traps are also stabilizers (whether it is the metal salt such as MgCO3 or the saccharide). This is the same purpose taught in Schwendeman ‘909 for the MgOH2. This is the specific common use that would prompt one skilled in the art to combine dextran sulfate and magnesium hydroxide, absent a demonstration of an unexpected effect.
Applicants argue that (3) each reference discloses numerous alternatives and provides no guidance to select the specific combination recited in claim 21. Desai discloses multiple ionic affinity traps and Schwendeman ‘909 discloses over a dozen basic additives.
Regarding Applicants’ third argument, while there are several alternatives disclosed, the list is still a finite list. All that is required to arrive at the instant invention is select a specific ionic affinity trap from those taught and a specific basic additive from those disclosed. Therefore, all of the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions and the combination would have yielded predictable results to one of ordinary skill in the art at the time of the invention. Note: MPEP 2143 KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ 2d 1385 (2007). While there are other equally as obvious combinations, absent a demonstration of an unexpected effect with the instant claimed combination, it is the examiner position that mere selected from a finite list renders the specifically claimed species obvious.
Applicants argue that (4) Desai directs the skilled artisan toward aluminum-based compounds by specifically identifying aluminum hydroxide and aluminum phosphate as particularly useful. There is no motivation to select Mg(OH)2 or dextran sulfate when aluminum slats are clearly preferred. Applicants argue the rejection is based on hindsight.
Regarding Applicants’ fourth argument, the rejection is made under 103 and does not need to exemplify all embodiments, only suggest. “Disclosed examples and preferred embodiments do not constitute a teaching away from the broader disclosure or non-preferred embodiment.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). MPEP 2123. Thus, the preference for aluminum salts does not take away from the teachings that dextran sulfate and magnesium hydroxide would be obvious choices. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Here the cited prior art teaches dextran sulfate and magnesium hydroxide as choices.
Applicants argue that (5) new claim 21 recites the biopolymer comprises high molecular weight dextran sulfate. It is argued that paragraphs 0070-0075 of the application describes that high molecular weight dextran sulfate minimizes leaching during encapsulation and results in high loading and encapsulation efficiency.
Regarding Applicants’ fifth argument, firstly, the fundamental requirement is that “any superior property must be unexpected to be considered as evidence of non-obviousness.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007). Nothing in the specification actually teaches that the results are unexpected. Furthermore, the examiner cannot agree that the inclusion of high molecular weight dextran sulfate increasing loading and encapsulation efficiency is unexpected. As set forth below both des Rieux et al. and Sadat et al. suggest this is the expected effect (see discussion below).
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Desai et al. (WO 2011088229, cited on PTO Form 1449) as evidenced by Steudle (Biophys J., 2011, cited in the Office action mailed on January 16 2025) and in view of Schwendeman et al. (US 20080182909) as applied to claims 21-23 and 32 above and in further view of des Rieux et al. (Journal of Controlled Release, 2011).
Applicant Claims
The instant application claims the dextran sulfate comprises high molecular weight dextran sulfate. The instant specification teaches high molecular weight dextran sulfate has a molecular weight of about 500 kDa (paragraph 0037).
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teaching of Desai et al. and Schwendeman et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Desai et al. teaches dextran sulfate, Desai et al. is silent to the molecular weight. However, this deficiency is cured by des Rieux et al.
Des Rieux et al. is directed to 3D systems delivering VEGF to promote angiogenesis for tissue engineering. Negatively charged nanoparticles encapsulating VEGF (vascular endothelial growth factor) were obtained with high efficiency by complex formation with dextran sulfate (abstract). Dextran sulfate utilized has a 500 kDa molecular weight (section 2.1). The dextran sulfate is taught as protecting and stabilizing VEGF (section 3.2).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Desai et al., Schwendeman et al. and des Rieux et al. with a reasonable expectation of success and utilize dextran sulfate with a molecular weight of 500 kDa. One skilled in the art would have been motivated dextran sulfate with this molecular weight as Desai et al. teaches the use of an ionic affinity trap such as dextran sulfate for sorbing an active such as a protein and for stability, des Rieux et al. teaches dextran sulfate with a 500 kDa molecular weight can be utilized for stabilization as well as sorbing proteins such as VEGF.
Claims 21-23 and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Stern et al. (USPGPUB No. 20120003736) in view of Desai et al. (WO 2011088229, cited on PTO Form 1449).
Applicant Claims
The instant application claims a porous self-healing biodegradable polymer matrix suitable for encapsulation of an active macromolecule selected from the net positively charged peptides and net positively charged proteins, wherein the matrix comprises a biodegradable polymer and has pores and wherein: a biopolymer is disposed within the pores; and a pH modifying species is disposed within the pores; wherein the biopolymer comprises dextran sulfate and is present at a level of greater than 0.5% and below 10% by weight based on the weight of the biodegradable polymer, and wherein the pH modifying species comprises Mg(OH)2 and is present at a level of 1% to 7% by weight based on the weight of the biodegradable polymer.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
Stern et al. is directed to methods for culturing undifferentiated cells using sustained release compositions. The sustained release composition is a PLGA (poly(DL-lactide-co-glycolide)) microspheres. These microspheres further contain dextran sulfate and magnesium hydroxide. Concentration of dextran sulfate range from about 5% (w/v) to about 0.001%. Concentrations of magnesium hydroxide can range from about 15% (w/v) to about 0.05% (claims 6, 8-9, 24, 26; paragraph 0085, 0094-0095). Encapsulated material is FGF2 which is basic fibroblast growth factor (a protein) (paragraph 0009, 0044, 0093 and claim 25).
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Stern et al. teaches PLGA microspheres with dextran sulfate and magnesium hydroxide, Stern et al. does not expressly teach a concentration of the PLGA specifically or that the microspheres has pores. However, this deficiency is cured by Desai et al.
Desai et al. is directed to active self-healing biomaterial system. Taught are methods and compositions that load and encapsulate an agent, such as a protein in a porous self-healing polymer. A delivery system includes a porous self-healing polymer, an ionic affinity trap within the pores of the self-healing polymer (claims 1, 3-5) and an agent associated with the ionic affinity trap (abstract and claims). Taught is a delivery system including a porous self-healing polymer, optionally a differentially soluble material such as a saccharide or disaccharide, and one or more ionic affinity traps and plasticizers. The differentially soluble material can be employed to obtain a porous self-healing polymer network and/or to stabilize the polymeric material. A self-healing polymer having a porous network, such as PLGA microspheres, can be prepared using established methods (paragraph 0090) In some embodiment the encapsulation efficiency is greater than 50% and, in some embodiments, greater than 99% with greater than 60, 70, 80, 90 and 95% also taught (paragraph 00104). Ionic affinity trap include zinc carbonate (ZnCO3) (paragraph 0034). Claimed ionic affinity traps include aluminum hydroxide, magnesium carbonate, etc. (claim 12). Other examples of ionic affinity traps include extracellular matrix-like materials include dextran sulfate, chitosan and hyaluronic acids (paragraph 00120). A differentially soluble material, such as a saccharide or similar material, can be used in forming the pores in the self-healing polymeric material. Useful saccharides include disaccharides such as sucrose and polysaccharides such as dextran and glycosaminoglycans such heparin. The saccharide can be used to stabilize an ionomer gel used as the ionic affinity trap (paragraph 00105). Exemplified amount of calcium phosphate (ionic affinity trap) is 3.4% (paragraph 00133) and aluminum hydroxide (i.e. alhydrogel, ionic affinity trap) is 2.3% (paragraph 00133) or 1.35% (paragraph 00130), 2.9% (paragraph 00131). Taught is sorbing an agent to an ionic affinity trap wherein a solid polymer matrix comprises the ionic affinity trap and an aqueous solution comprising the agent (claim 20). At least 90% of the agent in the sorbing step is sorbed to the ionic affinity trap (claim 39).Other examples include lysozyme encapsulated in PLGA containing 0, 1.5, 4.3 or 11% magnesium carbonate (paragraph 0071).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Stern et al. and Desai et al. and expect a porous self-healing biodegradable polymer matrix. Stern et al. teaches PLGA microspheres with dextran sulfate and magnesium hydroxide. Desai et al. teaches that PLGA is a self-healing polymer and the formation of microspheres with PLGA and an ionic affinity trap such as dextran sulfate can result in the porous particle wherein the pores contain the ionic affinity trap. Therefore, since Desai et al. teaches the formation of porous microspheres with the same material as the particles of Stern et al. there is a reasonable expectation of success.
Regarding the claimed amount of dextran sulfate and magnesium hydroxide, Stern et al. teaches an overlapping amount. 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). Note MPEP 2144.05.
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Stern et al. in view of Desai et al. as applied to claims 21-23 and 32 above and in further view of Sadat et al. (International Journal of Nanomedicine, 2012).
Applicant Claims
The instant application claims the dextran sulfate comprises high molecular weight dextran sulfate.
Determination of the Scope and Content of the Prior Art
(MPEP §2141.01)
The teachings of Stern et al. and Desai et al. are set forth above.
Ascertainment of the Difference Between Scope the Prior Art and the Claims
(MPEP §2141.02)
While Stern et al. teaches PLGA microspheres with dextran sulfate, Stern et al. is silent to the molecular weight of dextran sulfate. However, this deficiency is cured by Sadat et al.
Sadat et al. is directed to improved drug loading and antibacterial activity of minocycline-loaded PLGA nanoparticles by solid/oil/water ion pairing method. Taught are PLGA nanoparticles. It is taught that entrapment efficiency was increased when low molecular weight PLGA and high molecular weight dextran sulfate was used (abstract). High molecular weight dextran is 500,000 Da aka 500 kDa) ( page 223). Dextran sulfate (molecular weight 500,000) was the preferred choice for ion pairing because it allowed the highest drug loading and entrapment efficiency (conclusion). It is taught that Dextran sulfate is an ion pairing agent. If ion pairing formation is faster than polymer precipitation, the ion pairs could be trapped during particular precipitation. The significant increase in entrapment efficiency and drug loading using high molecular weight dextran sulfate indicates that the additional negative charges of dextran sulfate have further incorporated minocycline. This was due to an ion pairing mechanism. (Discussion, page 230 right column-231 left column).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Stern et al., Desai et al. and Sadat et al. and utilize high molecular weight dextran sulfate. One skilled in the art would have been motivated to utilize this type of dextran sulfate as the additional negative changes can lead to greater entrapment efficiency and drug loading as taught by Sadat et al. Since Stern et al. exemplifies the use of dextran sulfate, one skilled in the art would have a reasonable expectation of success.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 21-24 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10369106 in view of Schwendeman et al. (USPGPUB No. 20020009493). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims a porous self-healing biodegradable polymer matrix suitable for encapsulation of an active macromolecule selected from the net positively charged peptides and net positively charged proteins, wherein the matrix comprises a biodegradable polymer and has pores and wherein: a biopolymer is disposed within the pores; and a pH modifying species is disposed within the pores; wherein the biopolymer comprises dextran sulfate and is present at a level of greater than 0.5% and below 10% by weight based on the weight of the biodegradable polymer, and wherein the pH modifying species comprises Mg(OH)2 and is present at a level of 1% to 7% by weight based on the weight of the biodegradable polymer.
Patent ‘106 claims a porous self-healing polymer matrix suitable for encapsulation of an active macromolecules selected from net positively charged peptides and net positively charged proteins, wherein the matrix comprises a biodegradable polymer and has pores and wherein: a biopolymer is disposed within the pores; and a pH modifying species is disposed within the pores; wherein the biopolymer comprises a dextran sulfate and is present at a level of greater than 0.5% and below 10% by weight based on the weight of the biodegradable polymer, and wherein the pH modifying species comprises magnesium carbonate (MgCO3) and is present at a level of 1% to 7% by weight based on the weight of the biodegradable polymer (claim 1). The biodegradable polymer includes poly(lactide-co-glycolide) (claims 2-3). The active macromolecule encapsulated is claimed (claim 5).
Patent ‘106 claims a pH modifying species MgCO3 but does not claim Mg(OH)2. However, this deficiency is cured by Schwendeman et al.
Schwendeman et al. is directed to methods for stabilizing biologically active agents encapsulated in biodegradable controlled-release polymers. As claimed the biodegradable polymer is PLGA (claim 1). Claimed is a basic additive selected from magnesium carbonate, magnesium hydroxide, zinc carbonate, zinc hydroxide, etc. (claim 7). The basic additive is taught as stabilizing the agent encapsulated during biodegradation (paragraph 0012).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of patent ‘106 and Schwendeman et al. and either replace the MgCO3 of patent ‘106 with Mg(OH)2 or use Mg(OH)2 with the MgCO3 in patent ‘106 as both are known basic additives which can stabilize an active agent as taught by Schwendeman et al. Since Schwendeman et al. teaches the additive used with PLGA there is a reasonable expectation of success.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-10 of U.S. Patent No. 10369106 in view of Schwendeman et al. (USPGPUB No. 20020009493) as applied to claims 21-24 and 32 above and in further view of des Rieux et al. (Journal of Controlled Release, 2011). Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims the dextran sulfate comprises high molecular weight dextran sulfate.
The claims of Patent ‘106 are set forth above. While Patent ‘106 claims dextran sulfate, Patent ‘106 is silent to the molecular weight of the dextran sulfate. However, this deficiency is cured by des Rieux et al.
Des Rieux et al. is directed to 3D systems delivering VEGF to promote angiogenesis for tissue engineering. Negatively charged nanoparticles encapsulating VEGF (vascular endothelial growth factor) were obtained with high efficiency by complex formation with dextran sulfate (abstract). Dextran sulfate utilized has a 500 kDa molecular weight (section 2.1). The dextran sulfate is taught as protecting and stabilizing VEGF (section 3.2).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘106, Schwendeman et al. and des Rieux et al. with a reasonable expectation of success and utilize dextran sulfate with a molecular weight of 500 kDa. One skilled in the art would have been motivated to utilize dextran sulfate with this molecular weight as des Rieux et al. teaches dextran sulfate with a 500 kDa molecular weight can be utilized for stabilization as well as sorbing proteins such as VEGF.
Claims 21-24 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11607387 in view of Schwendeman et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims are set forth above.
Patent ‘387 claims a porous self-healing biodegradable polymer matrix suitable for encapsulation of an active macromolecule selected from net positively charged peptides and net positively charged proteins, wherein the matrix comprises a biodegradable polymer and has pores and wherein: a biopolymer is disposed within the pores; and a pH modifying species is disposed within the pores; wherein the biopolymer comprises dextran sulfate and is present at a level of greater than 0.5% and below 10% by weight based on the weight of the biodegradable polymer, and wherein the pH modifying species comprises ZnCO3 and is present at a level of 1% to 7% by weight based on the weight of the biodegradable polymer (claim 1). The biodegradable polymer includes poly(lactide-co-glycolide) (claims 2-3). The active macromolecule encapsulated is claimed (claim 4).
While Patent ‘387 claims a pH modifying species ZnCO3, Patent ‘387 does not claim Mg(OH)2. However, this deficiency is cured by Schwendeman et al.
The teachings of Schwendeman et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of patent ‘387 and Schwendeman et al. and either replace the ZnCO3 of patent ‘387 with Mg(OH)2 or use Mg(OH)2 with the ZnCO3 in patent ‘387 as both are known basic additives which can stabilize an active agent as taught by Schwendeman et al. Since Schwendeman et al. teaches the additive used with PLGA there is a reasonable expectation of success.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of U.S. Patent No. 11607387 in view of Schwendeman et al. as applied to claims 21-24 and 32 above and in further view of des Rieux et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims the dextran sulfate comprises high molecular weight dextran sulfate.
The claims of Patent ‘387 are set forth above. While Patent ‘387 claims dextran sulfate, Patent ‘387 is silent to the molecular weight of the dextran sulfate. However, this deficiency is cured by des Rieux et al.
The teachings of des Rieux et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘387, Schwendeman et al. and des Rieux et al. with a reasonable expectation of success and utilize dextran sulfate with a molecular weight of 500 kDa. One skilled in the art would have been motivated to utilize dextran sulfate with this molecular weight as des Rieux et al. teaches dextran sulfate with a 500 kDa molecular weight can be utilized for stabilization as well as sorbing proteins such as VEGF.
Claims 21-24, 32 and 41 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 6743446 in view of Desai et al. (WO2011088229, cited in the Office action mailed on January 16 2025) and des Rieux et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘446 claims a biodegradable polymeric delivery system for delivering biologically active agents encapsulated therein to a subject, wherein the biodegradable polymeric delivery system maintains a pH of greater than 3 during biodegradation of the polymeric delivery system over a period of 4 weeks, wherein said delivery system comprises a) a PLGA polymer b) from 0.5% to 20% by weight of a composition which comprises the agent or a combination of the agent and a carrier; and c) from 0.5% to 20% by weight of one or more basic additives selected from the group consisting of magnesium carbonate, magnesium hydroxide, magnesium oxide, magnesium trisilicate, zinc carbonate, zinc hydroxide, zinc phosphate, aluminum hydroxide, basic aluminum carbonate, dihydroxyaluminum sodium carbonate, dihydroxyaluminum aminoacetate, calcium phosphate, calcium hydroxide, magaldrate; and d) a microclimate which maintains a pH of greater than 3 during biodegradation of the polymeric delivery system for a period of 4 weeks (claim 16). The delivery system includes a pore forming agent (indicating the system is porous) (claim 20). The method of making includes a carrier which includes dextran (claim 6). The agent includes peptides/proteins (claim 17).
While Patent ‘446 claims dextran, patent ‘446 does not claim dextran sulfate. However, this deficiency is cured by Desai et al. and des Rieux et al.
Desai et al. teaches a solid polymer matrix comprising an ionic affinity trap which is operable to sorb an agent from an aqueous solution (claim 1). The matrix includes a polymer which can be a copolymer of lactic acid and glycolic acid (claim 9). Ionic affinity traps include dextran sulfate (paragraph 0120). This compound can be used to trap the agent (paragraph 0012).
The teachings of Des Rieux et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of patent ‘446, Desai et al. and des Rieux et al. and utilize dextran sulfate with the delivery system of patent ’446. One skilled in the art would have been motivated to utilize dextran sulfate in order to sorb agents (i.e. for use as an ionic affinity trap) as taught by Desai et al. One skilled in the art would have a reasonable expectation of success as Desai et al. teaches the use of dextran sulfate with PLGA polymer matrices and patent ‘446 claims dextran.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘446, Desai et al. and des Rieux et al. with a reasonable expectation of success and utilize dextran sulfate with a molecular weight of 500 kDa. One skilled in the art would have been motivated to utilize dextran sulfate with this molecular weight as des Rieux et al. teaches dextran sulfate with a 500 kDa molecular weight can be utilized for stabilization as well as sorbing proteins such as VEGF.
Claims 21-24 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of US Patent No. 12605448 (copending Application No. 17627878 (USPGPUB No. 20220257769)) in view of Schwendeman et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant claims are set forth above.
Patent ‘448 claims a porous self-healing polymer matrix for encapsulation of active macromolecules, wherein the active macromolecule comprises a peptide or a protein, the matrix comprising a biodegradable polymer and having pores and wherein: an ionic affinity trap is disposed within the pores; the ionic affinity trap comprises a metal ion, and the active macromolecule is covalently bound to a histidine tag. Biodegradable polymers include poly(lactide-co-glycolide) (claims 2-3). A biopolymer such as dextran sulfate, disposed within the pores is claimed (claims 4 and 10-11). Metal ions claimed include zinc.
While Patent ‘448 claims a metal ion in the pores, copending ‘878 does not expressly claim, Mg(OH)2. However, this deficiency is cured by Schwendeman et al.
The teachings of Schwendeman et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘448 and Schwendeman et al. and utilize Mg(OH)2 as the metal ions. One skilled in the art would have been motivated to use any of these metals as they are all known to stabilize an active agent as taught by Schwendeman et al. (i.e. binding a biopolymer as recited in claim 15). Since Schwendeman et al. teaches the additive used with PLGA there is a reasonable expectation of success.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of US Patent No. 12605448 (copending Application No. 17627878 (USPGPUB No. 20220257769)) in view of Schwendeman et al. as applied to claims 21-24 and 32 above and in further view of des Rieux et al. Although the conflicting claims are not identical, they are not patentably distinct from each other because both sets of claims overlap in scope.
The instant application claims the dextran sulfate comprises high molecular weight dextran sulfate.
The claims of Patent ‘448 are set forth above. While Patent ‘448 claims dextran sulfate, Patent ‘448 is silent to the molecular weight of the dextran sulfate.
However, this deficiency is cured by des Rieux et al.
The teachings of des Rieux et al. are set forth above.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Patent ‘448, Schwendeman et al. and des Rieux et al. with a reasonable expectation of success and utilize dextran sulfate with a molecular weight of 500 kDa. One skilled in the art would have been motivated to utilize dextran sulfate with this molecular weight as des Rieux et al. teaches dextran sulfate with a 500 kDa molecular weight can be utilized for stabilization as well as sorbing proteins such as VEGF.
Response to Arguments
Applicants’ arguments filed February 20 2026 have been fully considered but they are not persuasive.
Applicants argue that Schwendeman discloses over a dozen basic additives and the Office Action has not established why a person of ordinary skill in the art would select Mg(OH)2 from among these numerous alternatives to replace MgCO3 or ZnCO3 or selected Mg(OH)2.
Regarding Applicants’ arguments, while there are several alternatives taught in Schwendeman, the examiner cannot agree that this list isn’t a finite list. Since all of the alternatives, MgCO3 or ZnCO3 or Mg(OH)2 are taught for the same purpose, this amounts to simple substitution of one known alternative for another with a reasonable expectation of success. Applicants have not established an unexpected effect with regards to the Mg(OH)2.
Applicants argue that dextran and dextran sulfate are chemically distinct compounds with different properties. The Office action has not established why a person of skill in the art would modify the dextran of Patent ‘466 to use dextran sulfate instead.
Regarding Applicants’ argument, as set forth above, des Rieux et al. teaches that the inclusion of dextran sulfate leads to increased stabilization and encapsulation. While Patent ‘466 does claim dextran, the cited art provides motivation to utilize dextran sulfate in place of dextran as it is a known ion affinity trap and can increase stabilization and encapsulation of proteins. This is the motivation provided by the Office action with respect to the instant claims.
Conclusion
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/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636
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