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 1-17, 19-32, and 34-40 are pending, presented for examination, and rejected as set forth below.
Claim Interpretation
Applicants claims are directed to ring compositions comprising a core containing an ethylene vinyl acetate polymer (“EVA”) possessing defined properties containing, dispersed throughout the polymer, at least an aromatase inhibitor and a hydrophilic polymer, and an EVA membrane layer adjacent to and outer surface of the EVA core. Dependent Claim 2 places further limitations on the properties the EVA is to possess. Claims 4, 5, and 10 narrow thee identity and amount of EVA present in the composition. Claims 6-8, 11-16, and 20 place further limitations on the active agent, and additional active agents, present in the composition. Claims 3, 17, and 19 require the inclusion of additional components in the core composition. Claim 9 requires that the composition include “one or more compartments,’ which applicants specification indicates includes configurations where the core compositions is surrounded by a “membrane layer,” or membrane layers. (Specification paragraph [0068]). Claims 22-24 specify the inclusion, or absence, of therapeutic agents in the EVA membrane layer. Claims 25-32 place limitations on the identity and additional components present in the EVA membrane layer. Claims 34-37 require, and place various limitations on, the inclusion of a second membrane layer adjacent to the outer surface of the first membrane layer. Claims 38 and 39 recite “product-by-process” language concerning the manner in which the polymer compositions are manufactured: “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). Claim 40 utilizes a composition of Claim 1 in methods of treating disease.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 31 and 32 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Applicants Claims 31 and 32 specify that the first membrane polymer matrix of Claim 1 is to contain one or more hydrophilic compounds to control release of the agent from the ring device. As Claim 1 already specifies that the first membrane polymer matrix is to contain a plurality of water-soluble particles, it is unclear whether Claims 31 and 32 require an additional water-soluble particle or simply repeat the limitations imported from former Claim 21 into Claim 1.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 1-16, 19-22, 25, 27-32, and 34-40 are rejected under 35 U.S.C. 103 as being unpatentable over Pakkalin (CA2794790), in view of Ning (CN112315898)(machine translation provided; all references are to the machine translation), and Jukarainen (WO01/47490).
Pakkalin describes devices to be used for the treatment of, among others endometriosis addressing limitations of Claim 40, by the controlled release of an aromatase inhibitor, either alone or in combination with additional active agents including, for example, a gestagen to modulate estrogen receptors per the requirements of Claims 7 and 8. (Abs.). The preferred dosage form according to Pakkalin is a polymer composition in the form of an intravaginal ring comprising at least one compartment comprising a core and a membrane surrounding the core, which are either the same or different polymer compositions, and which deliver the aromatase inhibitor over a period of preferably 4-6 weeks, a range overlapping and therefore rendering obvious the release limitations of present claims 14 and 15. (Pg.1, 7), See 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.”). A typical daily dosage of aromatase inhibitors, more specifically the anastrozole of Claim 6, is 1 mg/day, or 0.1-0.9 mg/day, a range overlapping and therefore rendering obvious the release rate of instant claim 16. (Pg.3, 6, 9), see Peterson, supra. While no particular quantities of aromatase inhibitor such as are recited by Claims 11-13 are required by the teachings of Pakkalin, as the aromatase inhibitor is the active agent of the devices of Pakkalin, the selection of any particular dose or quantity of active agent amounts to little more than optimization of a result-effective parameter via routine experimentation, and considered obvious thereby. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where 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 a similar manner, while no particular concentrations of polymer or EVA are required by Pakkalin, as the polymer such as EVA is described as the matrix to be used to provide and control the release of the active agents so formulated, the selection of any particular concentration of EVA within the polymeric drug delivery device is prima facie obvious given the teachings of Pakkalin, addressing limitations of Claim 4. See Peterson, supra. Various physical configurations of the IVR are contemplated by the Pakkalin disclosure, including a core surrounded by multiple membranes, which may contain no active, or a different active than the aromatase inhibitor found in the core polymeric portion of the IVR. (Pg.12, 14). Pakkalin indicates that the core and membranes may be the same, or different, polymeric compositions, which may be either single polymers or combinations of polymers among which are included the EVA of the present claims, addressing limitations of Claims 1, 5, 9, 22, 25, and 34-39. (Pg.13). The inclusion of particulate materials and each of hydrophilic or hydrophobic materials to modify each of the hydrophilic or hydrophobic properties of the matrix to modify the rate of release of one or more of the therapeutic substances included in the IVR. (Pg.13). Again; while Pakkalin does not specify particular concentrations of hydrophobic or hydrophilic release-rate adjusting polymers to be included in the devices, by indicating that their inclusion effects the rate of release of agent from devices containing them, the selection of any particular concentration of these agents amounts to little more than optimization through routine experimentation and obvious thereby, addressing the limitations of Claims 3, 19, 27, 31, and 32. See Peterson, supra. Homogeneous distribution of the aromatase inhibitors throughout the polymer matrix is contemplated by the teachings of Pakkalin, addressing limitations of Claim 20. (Pg.14).
Pakkalin therefore describes IVR containing aromatase inhibitors and additional active agents including estrogen receptor modulators, provided in polymeric compositions made from EVA which are either provided as a matrix, or a matrix surrounded by one or more membranes which may contain active agents or not contain active agents and be formed from the same or different polymers from that of the core, designed to deliver about 1mg aromatase inhibitor per day for a period of 4-6 weeks, which contain either hydrophilic or hydrophobic components to modify the rate of release of the active agents contained therein, and their use in the treatment of endometriosis.
Pakkalin does not, however, specify that the EVA to be used conforms to the properties recited by Claims 1, 2, 5, 28, or 29, nor is the specific inclusion of a hydrophilic polymer as a portion of the matrix described.
This is cured in part by the teachings of Ning, which also describes vaginal ring controlled-release delivery systems of aromatase inhibitors homogeneously distributed through a core of an EVA polymer surrounded by EVA polymer membranes to provide controlled release of the aromatase inhibitor for periods of 28-42 days for the treatment of, among others endometriosis. (Pg.1-2). Ning indicates that a variety of EVA polymers find particular use in the formulation of both the core and film membranes of these rings, and in particular advocates that combining multiple different EVA polymers provides the skilled artisan to modify and improve the hardness and elasticity of the vaginal ring to greatly improve patient compliance. (Pg.3-4). Three different grades of EVA are particularly described for the skilled artisan to employ: EVA28 having a vinyl acetate concentration of 28%, melting temperature of 71C, and a melt flow index of 4.5; EVA33 having a vinyl acetate concentration of 33%, melting temperature of 62C, and a melt flow index of 45; and EVA40 having a vinyl acetate concentration of 40%, melting temperature of 54C, and a melt flow index of 55. (Pg.3). Each of these EVA polymers described by Ning as being used, either alone or in combination, to provide for the core or membranes of sustained release aromatase inhibitor releasing vaginal rings, satisfy the properties recited by instant claims 1, 2, 10, and 28-30, and fall within the generic teachings of Pakkalin concerning the use of EVA in the formulation of aromatase sustained-release vaginal rings. Ning advocates combinations of EVA provide for helpful modification to the hardness and elasticity of the rings so formulated. Each of Pakkalin and Ning indicate that the same, or different, EVA compositions may be used as the core and membrane materials of said intravaginal rings. The art at the time of the instant application therefore suggests not only the precise EVA polymers recited by applicants claims are known to be useful in the manufacture of intravaginal sustained-release aromatase inhibitor releasing rings for the treatment of endometriosis, but so too does the art suggest combining EVA polymers to provide either the matrix or membrane components of such rings, as well as suggesting that the core and membrane polymers may be either the same or different, and be configured in a manner where the membranes either contain, or lack, active agents.
Jukarainen also describes intravaginal devices for the extended release of active agents contained therein, including intravaginal rings. Pg.1; 15. While indicating that EVA polymers are commonly employed as matrix elements for these devices, Jukarainen also indicates that polysiloxanes, and more particularly hydrophilic modified polysiloxanes, are usefully incorporated into such EVA matrices. These polymers not only serve to modify the physical properties of the EVA polymer to increase flexibility, but also to act as a release-rate modifying adjunct in such EVA matrices, such as Pakkalin advocates the inclusion of. Pg.2-3. Jukarainen indicates that aromatase inhibitors are compatible with such polymeric matrices. Pg.24.
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 IVR containing aromatase inhibitors and additional active agents including estrogen receptor modulators, provided in polymeric compositions made from various grades of EVA which are either provided as a matrix, or a matrix surrounded by one or more membranes which may contain active agents or not contain active agents and be formed from the same or different polymers from that of the core, designed to deliver about 1mg aromatase inhibitor per day for a period of 4-6 weeks, which contain either hydrophilic or hydrophobic components including hydrophilic polymers such as PEO modified polysiloxanes to modify the rate of release of the active agents contained therein, and their use in the treatment of endometriosis from within the prior art, to arrive at compositions “yielding no more than one would expect from such an arrangement.”
Claims 1-16, 19-25, 27-32, and 34-40 are rejected under 35 U.S.C. 103 as being unpatentable over Pakkalin, Ning, and Jukarainen as applied to Claims 1-16, 19-22, 25, 27-32, and 34-40 above, and further in view of Janni (Wolfgang Janni & Philip Hepp, Adjuvant Aromatase Inhibitor Therapy: Outcomes and Safety, 36 Cancer Treat. Rev. 249 (2010)), and Harrison (WO02/09631).
Pakkalin, Ning, and Jukarainen suggest IVR containing aromatase inhibitors and additional active agents including estrogen receptor modulators, provided in polymeric compositions made from various grades of EVA which are either provided as a matrix, or a matrix surrounded by one or more membranes which may contain active agents or not contain active agents and be formed from the same or different polymers from that of the core, designed to deliver about 1mg aromatase inhibitor per day for a period of 4-6 weeks, which contain either hydrophilic or hydrophobic polymeric components to modify the rate of release of the active agents contained therein, and their use in the treatment of endometriosis.
Neither Pakkalin, Ning, nor Jukarainen suggest formulating the IVR to contain and release bisphosphonates.
Janni, however, indicates that it is well known that aromatase inhibitor therapy contributes to decreased bone density and increased risk of bone fractures, and that concomitant therapy with bisphosphonates is recommended as prophylaxis. (Pg.251-53). Harrison goes further, indicating that transvaginal delivery of bisphosphonates demonstrates increased bioavailability when compared to oral routes of administration. (Pg.5, 10). Daily bisphosphonate dosages delivered transvaginally include 1mg/day, 2.5mg/day, 0.5mg/day, values falling within and therefore rendering obvious the limitations of Claim 24. (Pg.21, 23, ). Vaginal rings represent a particular form of solid controlled-release drug delivery available to the skilled artisan. (Pg.31-32).
It would have been prima facie obvious to have included a bisphosphonate in the IVR suggested by Pakkalin, Ning, and Jukarainen owing to the fact that Janni establishes that aromatase inhibitor therapy has known detrimental effects on bone density and fracture frequency, and that bisphosphonate dosages falling within the ranges claimed are known to be useful in the treatment of bone density loss when delivered transvaginally.
Claims 1-17, 19-32 and 34-40 are rejected under 35 U.S.C. 103 as being unpatentable over Pakkalin, Ning, Jukarainen, Janni, and Harrison as applied to Claims 1-25, 27-32, and 34-40 above, and further in view of Ozguney (WO2019/083483).
Pakkalin, Ning, Jukarainen , Janni and Harrison suggest IVR containing combinations of bisphosphonates and aromatase inhibitors provided in polymeric compositions made from various grades of EVA which are either provided as a matrix, or a matrix surrounded by one or more membranes which may contain active agents or not contain active agents and be formed from the same or different polymers from that of the core, designed to deliver about 1mg aromatase inhibitor per day for a period of 4-6 weeks, which contain either hydrophilic polymers or hydrophobic components to modify the rate of release of the active agents contained therein, and their use in the treatment of endometriosis.
None of these references advocate the inclusion of a plasticizer in the intravaginal rings described.
However, Ozguney indicates that incorporating plasticizers provides improvements in preparation of extrusion products and increases the processability of polymers used to formulate polymeric vaginal implants. (Pg.2-3). As the IVR suggested by the combined teachings of Pakkalin, Ning, Jukarainen, Janni and Harrison are just such polymeric compositions, a skilled artisan would appreciate that including the plasticizers suggested by Ozguney would improve the processability of such polymeric compositions, rendering their inclusion prima facie obvious.
Response to Arguments
Applicant's arguments filed 14 May 2026 have been fully considered but they are not persuasive.
Applicants assert that the amendments to the claims address the previous rejection of Claims 31-33 as being indefinite. As the central conflict between the claims remains, namely whether the limitations of Claims 31 and 32 refer to an additional hydrophilic component of the first membrane composition to be present, this rejection is maintained.
Applicants again argue that the previous rejections fail to teach the limitation newly added to Claim 1. As a threshold matter, Applicants’ arguments are legally insufficient to properly raise an issue concerning the patentability of the invention claimed. In re Lovin, 652 F.3d 1349, 1357 (Fed. Cir. 2011) (“[T]he Board reasonably interpreted Rule 41.37 to require more substantive arguments in an appeal brief than a mere recitation of the claim elements and a naked assertion that the corresponding elements were not found in the prior art.”). Moreover, Applicants arguments are inaccurate because, as set forth previously and again above, Pakkalin indeed suggests providing multiple polymeric membranes surrounding a polymeric core, among which the EVA of the present claims is enumerated as a suitable membrane polymer, which may include or exclude a therapeutic agent, or which may incorporate hydrophilic particles to modify the properties of the polymer and alter the rate of release of agents from a device so coated. See Pakkalin pg.12-14. Contrary to applicants assertion, Pakkalin itself provides the rationale for providing an EVA layer atop the EVA core of the devices described. Moreover, applicants are reminded that 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). As such, it is irrelevant to the question of obviousness what particular problems Ning or Jukarainen may be attempting to solve within the totality of their disclosure, nor whether that differs from the goals of Pakkalin. Pakkalin generically describes the use of EVA polymers in the manufacture of IV ring devices, with Ning explaining how modifying the type and content of the EVA polymers in IV rings can contribute to improving patient compliance. Applicants are reminded that the strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95 (Fed. Cir. 1983). Improved patient compliance results in improved outcomes, rendering such a modification desirable and therefore prima facie obvious. In a similar manner, Jukarainen indicates that PEO modified polysiloxanes are hydrophilic compositions known to modify each of the release rates of agents from IV rings as well as alter the strength and flexibility of these devices, which Ning has established is a beneficial modification to such devices. The record therefore provides ample justification for modifying the IV rings of Pakkalin in the manner set forth by the Examiner, rendering the rings of the present claims a prima facie obvious modification of the prior art.
Applicants assert that PVP and PEO modified polysiloxanes are not interchangeable equivalents. The Examiner points out that nowhere in the record can be found an assertion by the Examiner that they are. The Examiner additionally reminds applicants that they have not recited PVP as a required component of the devices set forth by the claims. In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993) (although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims).
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.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614
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