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 .
Status of the Claims
Claims 12-16 and 21-28 are pending, presented for examination, and rejected as set forth below.
Claim Interpretation
Applicants’ claims are directed to methods of treating diseases or disorders, and more specifically as set forth by dependent Claims 13, 14, 15, and 16, diabetes mellitus type I, by the administration of a composition containing biodegradable particles encapsulating an antigen, and having any of a Markush-type listing of alternative immune modulator carbohydrate moieties covalently attached to the particle, the particle having a size within the range of 0.01-500 microns. Claim 21 requires the particles be provided with a carrier, excipient, or diluent. Claims 23-25 indicate that the carbohydrate be bound to the particle by a linker, ultimately indicating such limitations are addressed by a carbohydrate bound to the particle via a carbodiimide linker. Claims 26-28 indicates that an additional immunomodulator aside from the carbohydrate moiety selected from the Markush listing of Claim 12 is to be included. Claim 22 describes a result to be observed following the practice of the method of Claim 12: this does not represent an affirmative limitation of the method under examination because it is well established that a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005) (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
Claim Rejections - 35 USC § 103
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.
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 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 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 12-16 and 21-28 are rejected under 35 U.S.C. 103 as being unpatentable over Shi (U.S. PGPub. 2014/0037736) in view of Phillips (Jenny M. Phillips, et al, Type 1 Diabetes Development Requires Both CD4+ and CD8+ T Cells and Can Be Reversed by Non-Depleting Antibodies Targeting Both T Cell Populations, 6 Rev. Diab. Stud. 97 (2009)), Ludvigsson (Johnny Ludvigsson, The Role of Immunomodulation Therapy in Autoimmune Diabetes, 3 J Diab. Sci. Tech. 320 (2009)), Sanders (William J Sanders, et al, L-Selectin-Carbohydrate Interactions: Relevant Modifications of the Lewis X Trisaccharide, 35 Biochem. 14862 (1996)), and Yang (Xiao-Dong Yang, et al, Inhibition of Insulitis and Prevention of Diabetes in Nonobese Diabetic Mice by Blocking L-selectin and Very Late Antigen 4 Adhesion Receptors, 90 Proc. Natl. Acad. Sci. USA 10494 (1993)).
Shi describes synthetic nanocarriers for modulating the immune system. [0006]. Shi indicates that these polymeric nanocarriers may encapsulate any of the agents described in the disclosure, including insulin. [0014; 0581; 0586; 0589; 0600]. Particular embodiments include nanocarriers having diameters of, for example, between about 60-200nm, a range overlapping and therefore rendering obvious that of the instant claims. [0019], see also In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”). Shi indicates that targeted nanocarriers modified in a manner designed to target T cells or B cells, [0021-27], such as by the covalent bonding of carbohydrate moieties known to specifically bind to a desired target, fall within the metes and bounds of the technology described. [0305-08]. L-selectin is identified as a particular target for each of T and B cells as well as macrophages, establishing that Shi recognizes these moieties are known targets of T and B cells for the delivery of agents such as insulin. [0273; 0359; 0363]. PLGA is particularly described as a suitable biodegradable polymer used in the formation of the nanocarriers described, [0418], which additionally describes carbodiimide linking groups addressing Claims 22-25 as suitable for the covalent bonding of targeting or immunomodulatory moieties to the nanocarrier polymer. [0477-86]. Shi teaches that any of a variety of known and acceptable excipients of Claim 21 may be combined with the nanocarriers described, [0526-27], and specifically indicates that insulin may be associated with the nanocarriers described. [0586]. Shi recites insulin-dependent diabetes mellitus, otherwise known as the diabetes mellitus type 1 of the instant claims, as a suitable autoimmune disease treatable by the use of such targeted nanoparticles. [0520-27].
The specific combination of features claimed is disclosed within the broad generic ranges taught by the reference but such “picking and choosing” within several variables does not necessarily give rise to anticipation. Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989). Where, as here, the reference does not provide any motivation to select this specific combination of a selectin targeting carbohydrate linked via carbodiimide to a PLGA nanoparticle having a size in the range of about 60-200 microns combined with excipients and insulin, for use in the treatment of type 1 diabetes, anticipation cannot be found.
That being said, however, it must be remembered that “[w]hen a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious.” KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)). “[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious,” the relevant question is “whether the improvement is more than the predictable use of prior art elements according to their established functions.” (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 “need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” KSR at 1741. The Court emphasized that “[a] person of ordinary skill is… a person of ordinary creativity, not an automaton.” Id. at 1742.
Consistent with this reasoning, it would have been prima facie obvious to have selected various combinations of various disclosed ingredients ligands for L-selectin linked via carbodiimide to a PLGA nanoparticle having a size in the range of about 60-200 microns combined with excipients and encapsulating insulin to treat insulin-dependent diabetes mellitus from within a prior art disclosure, to arrive at compositions “yielding no more than one would expect from such an arrangement.”
Despite this, Shi does not provide a rationale for employing each of the Sialyl Lewis X or Sulfo Lewis X carbohydrates as the ligands for targeting the L-selectin receptor of T or B cells for the delivery of encapsulated insulin.
However, Sanders indicates that each of the sulfated and sialylated derivatives of the Lewis X carbohydrate have millimolar range affinities for L-selectin, while also demonstrating anti-inflammatory activity. (Pg.14862-3). Yang establishes that targeting L-selectin of pancreatic B-cells, T cells, and macrophages is known to act as antiinflammatory agents and treat diabetes. (pg. 10494; 97). This would have made it prima facie obvious to one of ordinary skill in the art to have selected either of the Sialyl Lewis X or Sulfo Lewis X carbohydrates as the ligands for targeting the L-selectin receptor of B cells in the treatment of diabetes by their use as B cell targeting ligands on the insulin containing PLGA nanoparticles suggested by Shi.
This conclusion is further supported by the disclosure of each of Phillips and Ludvigsson, which establish that targeting T cells with appropriate immunomodulators can reverse type 1 diabetes, as well as the fact that type 1 diabetes is characterized by a lack of insulin, rendering the T-cell targeted insulin containing nanoparticles of Shi an obvious selection of therapeutic agents for the treatment of type 1 diabetes mellitus.
Response to Arguments
Applicant's arguments filed 16 June 2026 have been fully considered but they are not persuasive.
As a threshold matter, applicants are reminded that it is not possible to establish the non-obviousness of an invention rendered obvious by the combined teachings of multiple prior art references by arguing that each of the references relied upon fails to teach the entirety of the invention which has been claimed; the absence of a single anticipatory reference is implied by both the reliance on the combined teachings of multiple references as well as the fact that the rejection being made is one of obviousness under 35 U.S.C. 103 rather than any of the subsections of 35 U.S.C. 102. MPEP § 2145(IV), see In re Keller, 642 F.2d 413, 426 (C.C.P.A. 1981) (citing Application of Young, 403 F.2d 754, 757 (C.C.P.A. 1968) (indicating that "[O]ne cannot show non-obviousness by attacking references individually where ... the rejections are based on combinations of references"). As such, the piecemeal analysis of various teachings provided the skilled artisan by each of the Shi, Phillips, Ludvigsson, Sanders, and Yang references accompanied by statements that they fail to teach the entirety of the invention claimed are unpersuasive. This is because applicants improperly expect each reference to teach the invention claimed when considered individually, rather than properly considering what the art of record, considered as a whole, conveys to the skilled artisan.
Applicants again assert that Shi lists a variety of agents capable of targeting T cells, B cells, and macrophages without guidance as to how or which targeting ligands to use, continuing on to indicate that carbohydrates are merely one among many classes of agents to be attached to PLGA particles for targeting purposes. This argument, advanced multiple times in the past, is no more persuasive upon its repetition. This is because not only does Shi establish the use of carbohydrates as targeting ligands for PLGA nanoparticles, but also because the rejections of record rely on more than Shi to establish the prima facie obviousness of employing insulin nanoparticles containing either of Sialyl or Sulfo Lewis X carbohydrates as targeting moieties. Applicants are once more reminded that it is not possible to establish the non-obviousness of an invention rendered obvious by the combined teachings of multiple prior art references by arguing that each of the references relied upon fails to teach the entirety of the invention which has been claimed; the absence of a single anticipatory reference is implied by both the reliance on the combined teachings of multiple references as well as the fact that the rejection being made is one of obviousness under 35 U.S.C. 103 rather than any of the subsections of 35 U.S.C. 102. MPEP § 2145(IV), see In re Keller, 642 F.2d 413, 426 (C.C.P.A. 1981) (citing Application of Young, 403 F.2d 754, 757 (C.C.P.A. 1968 (indicating that "[O]ne cannot show non-obviousness by attacking references individually where ... the rejections are based on combinations of references"). Here, Shi establishes that ligands targeting L-selectin are known to the skilled artisan as a moiety which, when bound to PLGA particles encapsulating agents such as insulin, may target each of T and B cells. The rationale as well as art relied on by the examiner establishes that each of Sialyl and Sulfo Lewis X carbohydrates target L-selectins, and that targeting of L-selectins in T cells, B cells, and macrophages contributes to both a reduction in inflammation and the treatment of diabetes. Such an arrangement of elements taught by the prior art would be particularly obvious given the knowledge conveyed by each of Phillips and Ludvigsson concerning the utility of targeting T and B cells in the treatment of type 1 diabetes mellitus. Thus it is the combined teachings of Shi, Sanders, Yang, Phillips, and Ludvigsson which establish not only the requisite rationale for choosing insulin as an agent encapsulated by PLGA as a particulate carrier to which is bound Sulfo-Lewis X as is required by the claims. See In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000)( the proper test for obviousness is what the combined teachings would have suggested to a person of ordinary skill in the art).
Applicants assertion that Sanders merely cites another reference for the fact that Sialyl groups possess inherent antiinflammatory properties without verification is unpersuasive. "[A] prior art publication cited by an Examiner is presumptively enabling barring any showing to the contrary by a patent applicant." In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012). As applicants provide no evidence tending to contradict the conclusions drawn on the basis of the evidence of record, this is unpersuasive.
Applicants arguments concerning Yang ignore the fact that the reference indeed indicates that targeting L-selectins on pancreatic B cells, T cells, and macrophages may be used for the treatment of insulin dependent diabetes mellitus, as well as the fact that Yang is not relied upon in a vacuum, but rather in combination with an abundance of art establishing the utility of Sialyl or Sulfo Lewis X carbohydrates for targeting L-selectins on a variety of cells involved in the pathogenesis of insulin-dependent diabetes mellitus.
Applicants repeatedly argue that nothing of the art of record establishes an expectation that PLGA nanoparticles encapsulating insulin and possessing either a Sulfo or Sialyl Lewis X carbohydrate would induce tolerance or IL-10 production in a subject to which they are administered ignores the fact that this language does not represent an affirmative step of the methods being claimed. These are in fact recitations of post-activity observation, or rather a scientific explanation of the prior art’s functioning. Applicants are reminded that Claim language is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951); see also Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005) (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003))(indicating that “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.”). Here, the method claimed is simply the administration of a particular composition to a particular patient population, namely a subject having type I diabetes. The recitation of a biological response which follows the administration of the composition representing the actual method steps required by the claims represents precisely such a recitation of a result to be achieved by the practice of the method steps positively recited, which cannot therefore serve to distinguish the otherwise obvious method suggested by the art. This is moreover even less persuasive when the fact that the art of record indeed establishes that the particles suggested by the combined teachings of Shi, Sanders, Yang, Phillips, and Ludvigsson would induce tolerance as is required by the claims. Applicants arguments concerning these results also appear to miscomprehend the objective reach of the claims. Here, it is important to recognize that the claims require the particles induce tolerance in response to the antigen, which is precisely what the teachings of Ludvigsson suggest the use of insulin in the treatment of type 1 diabetes will accomplish. As applicants have provided no evidence tending to suggest the arrangement of art-known elements according to the teachings of the art would in fact do anything other than what a skilled artisan would expect, their arguments concerning so-called unexpected results to be achieved by the practice of the invention claimed are unpersuasive.
Applicants arguments concerning the skilled artisan needing to “pick and choose” among the alternatives disclosed by Shi continues applicants error of attempting to assert that the entirety of the invention must be disclosed by each reference. This is not the law. Applicants are reminded that 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). Furthermore, it has long been held that “picking and choosing may be entirely proper in the making of a 103, obviousness rejection, where the applicant must be afforded an opportunity to rebut with objective evidence any inference of obviousness.” In re Arkley, 455 F.2d 586, 587-88 (CCPA 1972). That Shi describes embodiments which do not read on, or run contrary to, the instant invention is immaterial to the question of obviousness. The test for obviousness is not whether the features of a reference may be bodily incorporated into the structure of the remaining references; 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).
Applicants repeated arguments concerning the induction of tolerance repeat arguments previously considered and deemed unpersuasive. Applicants discussion of art not relied upon by the examiner concerning compositions not relied upon by the examiner in an attempt to establish that these unrelated compositions are inflammatory, rather than anti-inflammatory, fail to address the fact that the art of record establishes an expectation that these particular carbohydrates are in fact described as anti-inflammatory, as are a variety of other carbohydrates. See, e.g., Laura Cipolla, et al, Discovery and Design of Carbohydrate-Based Therapeutics, 5 Exp. Opin. Drug Discov., 721 (2010); Hailong Zhang, et al, Recent Developments in Carbohydrate-Decorated Targeted Drug/Gene Delivery, 30 Med. Res. Rev. 270 (2010); Edward Young, The Anti-Inflammatory Effects of Heparin and Related Compounds, 122 Thromb. Res. 743 (2008). The skilled artisan would therefore come to understand that the inflammatory, or anti-inflammatory, nature of a carbohydrate would depend not on merely being identifiable as a carbohydrate, but rather on the particular structure and properties the carbohydrate in question possesses.
For at least these reasons, applicants arguments are unpersuasive.
Conclusion
No Claims are allowable.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN M BASQUILL whose telephone number is (571)270-5862. The examiner can normally be reached Monday through Thursday, 5:30 AM to 4 PM.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571) 272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614
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