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 .
Claim Objections
Claim 2 is objected to because of the following informalities:
In relation to claim 2:
the phrase "more than one a layer" is grammatically incorrect; should be: "more than one layer" (remove the "a");
correct to "wherein the membrane comprises more than one layer of biocompatible porous polymer."
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 6, 8, 10, 11, and 15 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.
In relation to claim 5, this claim is indefinite under 35 U.S.C. § 112(b) because "the porous biocompatible polymer" lacks proper antecedent basis. Claim 1 does not introduce "a porous biocompatible polymer," making it unclear what "the porous biocompatible polymer" refers to.
In relation to claim 6, this claim is indefinite under 35 U.S.C. § 112(b) because "the layer of porous biocompatible polymer" lacks proper antecedent basis. Claim 1 does not introduce any "layer," making it unclear what "the layer" refers to.
In relation to claim 8, this claim is indefinite under 35 U.S.C. § 112(b) because claim 1 introduces "a membrane" but does not explicitly characterize it as "porous biocompatible". While claim 1 states that "the membrane comprises pores," which could be interpreted as making it "porous," and the chamber is "biocompatible," it is not clear that these modifiers can be directly applied to "the membrane" without explicit statement.
In relation to claim 10, this claim is indefinite under 35 U.S.C. § 112(b) because Claim 1 introduces "a biocompatible implantable chamber" and "a closed shell" but never uses the term "pouch." The term "the pouch" appears without any prior introduction. Using "the pouch" without first introducing "a pouch" violates antecedent basis requirements.
In relation to claim 11, as mentioned in the analysis of clam 10, this claim is indefinite under 35 U.S.C. § 112(b) because because "the pouch" lacks proper antecedent basis.
In relation to claim 15, this claim is indefinite under 35 U.S.C. § 112(b) because "the membranes" (plural) lacks proper antecedent basis. Claim 1 introduces only "a membrane" (singular), creating ambiguity about whether the chamber comprises one or multiple membranes.
In relation to the lack of antecedent problems in claims 5, 6, 8, 10, 11, and 15, 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.
Claims 1, 3, 4, 6, 7, 9, 10, 15, 16, 17, 18, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Brauker et al. (US 5,807,406; hereinafter “Brauker '406”) in view of Brauker et al. (US 7,192,450; hereinafter “Brauker '450”) and Mannuzza et al. (US 6,740,501; hereinafter “Mannuzza”).
Independent claim 1 discloses:
A biocompatible implantable chamber, comprising a closed shell made of a membrane,
delimiting an inner space, wherein the membrane comprises pores on at least one part of its surface, and wherein the pores are homogeneously distributed on the at least one part
of the membrane, and wherein the diameter of the pores is comprised between 200 nm
and 100 μm.
In relation to independent claim 1, Brauker '406 discloses a biocompatible implantable chamber [receptable or pouch] (Brauker '406, Abstract; figures 1B and 1C), comprising a layered porous polymer membrane structure (Brauker '406, col. 2, lines 50-51). However, Brauker '406 does not explicitly disclose that the pores are (a) homogeneously distributed or (b) that the pore diameter is between 200 nm and 100 μm. Brauker '450 teaches porous membranes for use with implantable devices (Brauker '450, Title). Brauker '450 discloses that the membrane can have pore sizes (referred to as cavity sizes) ranging from approximately 90 microns (Brauker '450, column 2, lines 63-64) to 1000 microns (Brauker '450, col. 4, lines 59-61). This range overlaps with the upper end of the range recited in claim 1 (200 nm to 100 μm, i.e., 0.2 μm to 100 μm).
Based on the above teachings, it would have been obvious to one of ordinary skill in the art (POSA) at the time the invention was filed to modify the semi-permeable membrane of Brauker '406 to incorporate the specific pore sizes taught by Brauker '450. Both references are in the field of implantable medical devices and concern the control of substance transport and tissue interaction. A POSA would have been motivated to select specific pore sizes, such as those taught by Brauker '450, to optimize the diffusion rate of the therapeutic agent from Brauker '406's pouch and to control the level of tissue ingrowth, thereby achieving a desired therapeutic effect and long-term device performance. The selection of a pore size within the ranges known in the art, including the overlapping range taught by Brauker '450, would have been a matter of routine optimization for a POSA.
Concerning the distribution of the pores, Mannuzza teaches a membrane for use in assessing cell invasion, wherein the membrane is a track-etched polycarbonate filter (Mannuzza, col. 2, lines 48-59). Mannuzza discloses that a key feature of this membrane is the "uniform distribution" of pores (Mannuzza, col. 5, lines 20-27). It is well-known in the art that track-etching is a process that results in pores that are highly uniform in size and distribution.1
An artisan skilled in the art seeking to create the implantable device of Brauker '406 with predictable and reliable diffusion characteristics would have been motivated to manufacture the membrane with a homogeneous or uniform pore distribution as taught by Mannuzza. A random distribution, as is common with other membrane formation techniques, can lead to inconsistent diffusion rates across the membrane surface and can create areas of mechanical weakness. Mannuzza teaches the desirability of uniform pore distribution for achieving even cell migration, which is analogous to achieving even and predictable diffusion of a therapeutic agent. Therefore, it would have been obvious to a POSA to apply the teaching of uniform pore distribution from Mannuzza to the implantable chamber of Brauker '406 to ensure consistent drug delivery and improve the mechanical integrity and reliability of the device.
In conclusion, it would have been obvious to an artisan of ordinary skill in the art at the time of filing to combine the teachings of Brauker '406, Brauker '450, and Mannuzza to arrive at the invention of claim 1. The combination of an implantable chamber (Brauker '406) with a specific, overlapping pore size range (Brauker) and a homogeneous pore distribution (Mannuzza) would have been a predictable and obvious design choice to optimize the performance of an implantable drug delivery device.
In relation to claim 3, as established in the rejection of claim 1, the combination of Brauker '406, Brauker '450, and Mannuzza teaches all limitations of claim 1. The membrane disclosed by Brauker '406 is a single semi-permeable membrane forming the pouch (Brauker '406, Col. 30, lines 21-26). It would have been obvious to POSA that the membrane of the combined teachings could be a single layer, as this represents the simplest and most direct configuration for the device. The prior art does not teach away from using a single layer; in fact, it is the default and most straightforward implementation. Therefore, arriving at a device with a single layer membrane would have been an obvious design choice for a person of ordinary skill in the art.
In relation to claim 4, as established in the rejection of claim 1, the combination of Brauker '406, Brauker '450, and Mannuzza teaches a biocompatible implantable chamber with a porous membrane.
Brauker '450 further teaches that the membrane of an implantable device can be made from a variety of biocompatible polymers, including silicone, polyurethane, a block copolymer, polytetrafluoroethylene, polyethylene-co-tetrafluoroethylene, polyolefin, polyester, polycarbonate, and others (Brauker '450, Col. 28, lines 29-48). This list explicitly discloses the majority of the polymers recited in claim 4 (polycarbonate, polyurethane, polyolefins, polyester, and fluoropolymers like polytetrafluoroethylene).
It would have been obvious to a person of ordinary skill in the art to select a suitable polymer from the list of known biocompatible materials taught by Brauker '450 for the construction of the membrane in Brauker '406's device. The selection of a specific material from a known list of suitable candidates to achieve desired properties such as biocompatibility, durability, and permeability is a matter of routine design choice and optimization for a POSA in the field of implantable medical devices.
In relation to claim 6, as discussed above, the combination of Brauker '406, Brauker '450, and Mannuzza teaches a biocompatible implantable chamber with a uniformly porous membrane. While these references do not explicitly disclose the exact pore density range of claim 6, it is well-known in the art of membrane filtration and diffusion that pore density is a critical parameter that is routinely optimized to control the flux across the membrane. Track-etched membranes, as taught by Mannuzza, are known to be available in a wide range of pore densities, including the range recited in the claim.
A person of ordinary skill in the art, in designing the implantable chamber of Brauker '406 for a specific therapeutic application, would have found it obvious to select a membrane with a particular pore density to achieve the desired rate of drug delivery. A higher density would allow for a higher diffusion rate, while a lower density would provide a more restricted flow. The selection of a pore density between 10³ and 10⁹ pores/cm² would have been a matter of routine experimentation and optimization for a POSA to achieve a predictable and therapeutically effective outcome, and therefore, would have been an obvious design choice.
In relation to claim 7, as discussed above, the combination of Brauker '406, Brauker '450, and Mannuzza teaches a biocompatible implantable chamber with a uniformly porous membrane. While the references may not explicitly disclose the exact thickness range of claim 7, membrane thickness is a fundamental design parameter that is balanced against mechanical strength and diffusion rate. A POSA would have understood that the membrane must be thick enough to provide sufficient structural integrity for a long-term implant, yet thin enough to allow for adequate diffusion of the therapeutic agent. The range of 5 μm to 250 μm is a conventional and well-known range for implantable polymeric membranes. For example, Brauker '450 discusses membrane thicknesses for its implantable device, noting that the second domain can have a thickness from about 1 micron to 100 microns (Brauker '450, Col. 29, lines 63-67 to Col. 30, lines 1-3). A POSA would have found it obvious to select a membrane thickness within this conventional range to balance the competing requirements of strength and permeability. This selection would have been a matter of routine optimization and not an inventive step.
In relation to claim 9, as established in the rejection of claim 1, the combination of Brauker '406, Brauker '450, and Mannuzza teaches a biocompatible implantable chamber with a uniformly porous membrane. Brauker '450 teaches a pore size range of 90 microns to 370 microns (Brauker '450, Claim 9), which overlaps with the range recited in claim 9 (5 μm to 100 μm). It is well within the ordinary skill in the art to select a pore size suitable for a particular application. The field of cell encapsulation and implantable devices widely recognizes that different pore sizes are required to allow the passage of therapeutic molecules while preventing the entry of immune cells. A POSA would have found it obvious to select a pore size within the 5 μm to 100 μm range, a standard range for such applications, to optimize the performance of the device taught by the combination of Brauker '406, Brauker '450, and Mannuzza. This selection would be a matter of routine optimization, not an inventive step.
In relation to claim 10, as discussed above, the combination of Brauker '406, Brauker '450, and Mannuzza teaches the implantable chamber of claim 1. Brauker '406 itself explicitly discloses the capability of using the implantable pouch in “association” with a catheter which would inherently require a port to connect the pouch to the catheter (Brauker '406, Col. 5, lines 52-57). Therefore, it would have been obvious to a person of ordinary skill in the art to include a connector port on the pouch, as this is a fundamental and well-known component for filling or flushing such devices. The inclusion of such a port is a simple and obvious mechanical addition to facilitate the intended use of the device.
In relation to claims 15, 16, 17, 18, and 26, these claims recite methods for administering substances (insulin, coagulation factors) to a patient using the chamber or pouch of claim 1, with various implantation locations. As discussed above, the combination of Brauker '406, Brauker '450, and Mannuzza teaches the implantable chamber of claim 1 for the administration of therapeutic substances
wherein the substance could be delivered “in association with” a catheter (Brauker '406, Col. 5, lines 52-57) and diffuses through the pores of the membrane (Brauker '406, Col. 1, lines 35-40).
In relation to the areas of the body where the apparatus can be implanted, it is the size of the space within the human body and the corresponding size of the pouch that determine where can be implantation take place within the human body. Accordingly, the actual location for implantation within the body is an obvious choice based on the size of the area within the body. In relation to the types of drugs to be use in combination with the pouch, this is a matter of experimentation based on the qualities of the drug and the medical needs of the patient. Therefore, since all the drugs mentioned in the claims in question are well-known in the art, its use in combination with the pouch would have been considered an obvious alternative in the use of the pouch based on the medical needs of the patient.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Brauker et al. (US 5,807,406; hereinafter “Brauker '406”) in view of Brauker et al. (US 7,192,450; hereinafter “Brauker '450”) and Mannuzza et al. (US 6,740,501; hereinafter “Mannuzza”), as discussed above, and in further view of Bou Aoun et al. (WO2015/086550A1; hereinafter “Bou Aoun '550”).
In relation to claim 2, as established in the rejection of claim 1, Brauker '406, Brauker '450, and Mannuzza teach all limitations of claim 1. Brauker '406's membrane is not explicitly limited to a single layer.
Bou Aoun '550 teaches a chamber for encapsulating secreting cells, wherein the membrane comprises at least two layers: a layer of porous biocompatible polymer and a layer of non-woven biocompatible polymer (Bou Aoun '550, Abstract; Claim 1). The motivation for using a multi-layer membrane is to improve the mechanical resistance of the implantable device (Bou Aoun '550, page 3, first paragraph, and page 4, lines 1-3).
Based on the above teachings, a POSA, seeking to improve the durability and mechanical strength of the implantable chamber of Brauker '406, would have found it obvious to incorporate a multi-layer membrane structure as taught by Bou Aoun '550. The use of multiple layers to enhance strength and control diffusion properties is a common and well-established principle in membrane and material science. Therefore, it would have been an obvious modification to the device of Brauker '406, as modified by Brauker '450 and Mannuzza, to construct the membrane from more than one layer to enhance its robustness for long-term implantation, as suggested by Bou Aoun '550.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Brauker et al. (US 5,807,406; hereinafter “Brauker '406”) in view of Brauker et al. (US 7,192,450; hereinafter “Brauker '450”) and Mannuzza et al. (US 6,740,501; hereinafter “Mannuzza”), as discussed above, and in further view of Legeay et al. (US 20040137063; hereinafter “Legeay '063”).
In relation to claim 5, as established, Brauker '406, Brauker '450, and Mannuzza teach a biocompatible implantable chamber with a porous membrane. However, these references do not explicitly teach the specific hydrophilic modification recited.
Legeay '063 teaches a semi-permeable membrane for a cell encapsulation chamber, wherein the membrane is made of a biocompatible film of porous polycarbonate surface modified by creation of polar sites and covered with a layer of at least one hydrophilic polymer (Legeay '063, Abstract). The motivation for this modification is to improve biocompatibility, reduce protein adsorption, and prevent cell adhesion, thereby enhancing the long-term performance of the implantable device (Legeay '063, paragraph [0020]).
Based on the above teachings, a person of ordinary skill in the art, when designing the implantable chamber or pouch, would have been aware of the challenges of biofouling and foreign body response. To improve the biocompatibility and functional lifetime of the device, it would have been obvious to apply a surface modification to make the membrane more hydrophilic, as taught by Legeay '063.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Brauker et al. (US 5,807,406; hereinafter “Brauker '406”) in view of Brauker et al. (US 7,192,450; hereinafter “Brauker '450”) and Mannuzza et al. (US 6,740,501; hereinafter “Mannuzza”), as discussed above, and in further view of Legeay et al. (US 20130131828; hereinafter “Legeay '828”).
In relation to claim 8, as discussed above, the combination of Brauker '406, Brauker '450, and Mannuzza teaches a biocompatible implantable chamber with a uniformly porous membrane. These references do not teach the specific coating with a biologically active molecule.
Legeay '828 teaches a functionalized semi-permeable membrane for a cell encapsulation
chamber, wherein the membrane comprises at least two layers, each comprising a hydrophilic polymer and at least one biologically active molecule (Legeay '828, Abstract). The description further clarifies that these molecules can be covalently bound to the surface to improve biocompatibility and induce desired biological responses, such as promoting vascularization or preventing inflammation (Legeay '828, paragraph [[0012]).
A person of ordinary skill in the art, seeking to enhance the integration and long-term
function of the implantable chamber of Brauker '406, would have found it obvious to incorporate biologically active molecules onto the membrane surface as taught by Legeay '828. The motivation is clearly provided in Legeay '828: to improve the device's interaction with the host tissue. Covalently binding these molecules to a hydrophilic polymer layer is a known method for surface functionalization. Therefore, adding such a functional coating to the membrane of the primary combination would have been a predictable and obvious step for a POSA to improve the device's biocompatibility and efficacy.
Claims 11, 12, 13, and 14 are rejected under 35 U.S.C. 103 as being unpatentable over Brauker et al. (US 5,807,406; hereinafter “Brauker '406”) in view of Brauker et al. (US 7,192,450; hereinafter “Brauker '450”) and Mannuzza et al. (US 6,740,501; hereinafter “Mannuzza”), as discussed above, and in further view of Bou Aoun et al. (WO 2018/087102A1; hereinafter “Bou Aoun '102”).
In relation to claims 11-14, the combination of Brauker '406, Brauker '450, and Mannuzza teaches the implantable chamber of claim 1. The concept of providing medical devices in a kit form with necessary accessories is conventional in the medical field. Bou Aoun '102, which is from the same applicant as the present application, explicitly discloses a kit that meets the limitations of claims 11-14. Specifically, Bou Aoun '102 teaches:
Claim 11: A kit comprising an implantable chamber with a connector and a catheter
that connects to the connector and a source of delivery (Bou Aoun '102, Claim 1).
Claim 12: The catheter can present an injection port, in particular one that is
implantable subcutaneously (Bou Aoun '102, page 2, lines 30-31).
Claim 13: The kit can further comprise a pump or syringe for sending the compound of
interest (Bou Aoun '102, page 4, lines 21-23).
Claim 14: The kit can further comprise sensors to measure biomarkers and send signals
to the delivery source (Bou Aoun '102, page 4, lines 19-20).
Based on the teachings above, it is a standard and obvious practice in the medical device
industry to package related and necessary components together in a kit for the convenience of the end-user (the surgeon or physician). A POSA would have found it obvious to package the chamber of the primary combination with the necessary catheter, port, and pump/syringe as taught by Bou Aoun '102 to provide a complete and ready-to-use system for the intended therapeutic purpose.
Claims 19, 20, 21, 23, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Brauker et al. (US 5,807,406; hereinafter “Brauker '406”) in view of Brauker et al. (US 7,192,450; hereinafter “Brauker '450”) and Mannuzza et al. (US 6,740,501; hereinafter “Mannuzza”), as discussed above, and in further view of Boulikas (US 6,511,676).
In relation to claims 19, 20, 21, 23, and 25, these claims recite methods for administering specific chemotherapy or anticancer drugs for the treatment of cancer, including brain cancer (glioblastoma), using the chamber of claim 1, with intra-parenchymal implantation.
As established, the combination of Brauker '406, Brauker '450, and Mannuzza teaches the implantable chamber of claim 1. In relation to the areas of the body where the apparatus can be implanted [claims 20 and 25], it is the size of the space within the human body and the corresponding size of the pouch that determine where can be implantation take place within the human body. Accordingly, the actual location for implantation within the body is an obvious choice based on the size of the area within the body.
In relation to the types of drugs to be use in combination with the pouch [19, 21, and 23], Boulikas teaches liposome encapsulated cisplatin for use in killing tumor cells (Boulikas, Abstract). The delivery of these known anticancer drugs via an implantable device to provide sustained, localized therapy is a well-established concept in the field of oncology. A person of ordinary skill in the art would have found it obvious to use the implantable delivery system of Brauker '406 to deliver any number of well-known chemotherapeutic agents, including those listed in claims 19, 21, 23, to treat various types of cancers. The motivation is clear: to provide targeted drug delivery to the tumor site, thereby increasing efficacy and reducing systemic toxicity. This is a fundamental goal of cancer therapy. The selection of a specific, well-known anticancer drugs for delivery via an established implantable pump system would have been an obvious and predictable application of known technologies to solve a known problem.
Conclusion
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Respectfully submitted,
/MANUEL A MENDEZ/ Primary Examiner, Art Unit 3783
1 Kaya et al., Track-Etched Nanoporous Polymer Membranes as Sensors: A Review, Journal of the Electrochemical Society, Volume 167, Number 3, published 21 January 2020. In the section titled “Etching of the Tracks”, the article discloses “[i]t was shown that exposing the track membranes to UV light prior to chemical etching, increases the track etching rate by sensitizing the tracks and allows for more homogeneous size distribution of the nanopores.”