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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/31/2026 has been entered.
Status of Action/Claims
Receipt of Remarks/Amendments filed on 3/31/2026 is acknowledged. Claims 1, 8, 9, 29, 30, 31, 33-34, 38-39, 45-49, 51-57 and 59-67 are pending in this application. Claims 57 and 59-64 have been withdrawn. Accordingly, claims 1, 8, 9, 29, 30, 31, 33-34, 38-39, 45-49, 51-56 and 65-67 are presented for examination on the merits for patentability.
Rejection(s) not reiterated from the previous Office Action are hereby withdrawn. The following rejections are either reiterated or newly applied. They constitute the complete set of rejections presently being applied to the instant application.
Withdrawn Rejection(s)/Objection(s)
The previous claim objections of claims 52, 54, 56, 64 have been withdrawn due to appropriate claim amendments.
Claims Interpretation
Claims 1, 29 and 31 recite the semi-permeable membrane preferentially retains PEG while allowing diffusion of protein. The use of the language “preferentially” in the recitation suggests that the retaining of PEG is optional or preferred but not required by the claim. Thus, the examiner interprets that the claims do not require that the semi-permeable membrane preferentially retains PEG while allowing diffusion of protein and that this limitation is optional.
New/Maintained Claim Objection(s) / Rejection(s)
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 8, 9, 29, 30, 31, 33-34, 38-39, 45-49, 51-56 and 65-67 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1, 29 and 31 recite the semi-permeable membrane preferentially retains PEG while allowing diffusion of protein. The instant specification does not disclose specifically what membrane comprised in the formulation allows permeation of the protein but is impermeable to PEG. Paragraph 30 of instant specification state that the open biphasic system allows for a semi-permeable membrane or other porous structure to preferentially retain PEG while allowing diffusion of protein. Paragraph 31 of specification states an example of an open system is a device with porous walls that allows the soluble form of the protein to have access to the outside environment. The specification does not disclose or describe how an open system with porous walls prevent the PEG from diffusing out of the pores but allows the protein to diffuse out, especially since PEG is water soluble. The specification do not disclose the specific membrane which retains PEG and allows the protein to diffuse out and the specification also do not clearly describe how an open system with porous wall allows the protein to diffuse out but not PEG. Applicant’s disclosure, as discussed above, does provide support for the pharmaceutical formulation comprising a semi-permeable membrane and if it is the semi-permeable membrane or porous wall which allows the active agent to diffuse out and PEG to be retained, then a prior art which teaches there being a semi-permeable membrane or diffusion pores would read on this function of PEG being retained while the active agent being diffused out.
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 1, 8, 9, 29, 30, 31, 33-34, 38-39, 45-49, 51-56 and 65-67 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.
Claims 1, 29 and 31 recite the semi-permeable membrane preferentially retains PEG while allowing diffusion of protein. The phrase "preferentially" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claims 8, 9, 30, 33-34, 38-39, 45-49, 51-56 and 65-67 are included in the rejection as they depend on a rejected base claim and do not clarify the issues discussed above.
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 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 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.
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 1, 8, 9, 29, 30, 31, 33-34, 38-39, 45-49 and 65-67 are rejected under 35 U.S.C. 103 as being unpatentable over Guo (US 2014/0363482; Dec. 11, 2014) in view of Herrmann (Pharmaceutical Research, Vol. 24, No. 8, Pg. 1527-1537; August 2007) and de Juan, JR. et al. (US 2012/0095439 A1; Apr. 19, 2012).
Guo, throughout the reference, teaches a bioerodible (i.e., biodegradable) sustained released drug delivery system that include biocompatible fluid and biocompatible solid core components (Para 0003). Guo teaches a drug delivery system comprising an inner core, which comprises a biocompatible fluid component and a biocompatible solid component and at least one agent dispersed, suspended or dissolved within the inner core (i.e., solid or fluid component, which encompasses there being less than 50% of the agent in liquid component), wherein the agent can be a peptide or a protein (Pg. 8, claim 44, line 1-6). The concentration of the agent in the inner core is at least 10% (Para 0035), which through straightforward calculation equates to 100 mg/ml and thus completely overlaps the claimed limitation in instant claim 1. The agent may be in granular (i.e., solid) form or the agent can be combined with a pharmaceutically acceptable carrier (Para 0056). The pharmaceutically acceptable carrier includes polyethylene glycol (Para 0082). Guo further teaches the biocompatible fluid component can be comprised of polyethylene glycol (Pg. 8, claim 45, line 1-2). Furthermore, Guo teaches the invention provides a polymer drug delivery system comprising an inner core or reservoir that contains a therapeutically effective amount of an agent. The drug delivery system comprises a first coating layer, surrounding the inner core, that is impermeable, negligibly or partially permeable to the agent and, optionally, a second coating layer that is permeable or semi-permeable to the agent and contain diffusion pores that allow the drug to diffuse from the core out of the system (Para 0005 and 0008). Guo, throughout the reference, teaches the agent having access to physiological fluid. As stated in paragraph 0036, the system is injected or inserted into a physiological system (e.g., a patient). Through semi-permeable layer, the agent has access to physiological fluid and one of the factors that determine the rate of release is the potential gradient of the agent from the core to the surrounding physiological fluid (Para 0008). Thus, Guo is teaching the protein agent diffused through the semi-permeable membrane to the outside aqueous environment. Furthermore, Guo teaches that upon injection or insertion, the delivery system will contact water or other immediately surround physiological fluid that will enter the polymer system (through semi-permeable membrane) and contact the inner core (para 0036).
In addition, Guo teaches that biocompatible solid and/or biocompatible fluid component of the core may dissolve when in contact with physiological fluid and the dissolving rate can be slow (e.g., less than 10% over a period of 24 hours, or even over a period of multiple days, weeks, or even months) (Para 0047). This reads on the formulation releasing the active over a period of time (e.g., 60 days) as recited in instant claims.
Guo teaches the concentration of the agent (i.e., protein) in the inner core is at least 10% or preferably over 50% and more preferably over 75% (Para 0035), which through straightforward calculation equates to between 100 mg/ml and more than 750 mg/ml. This concentration overlaps the instantly claimed amount of protein in the formulation.
With respect to claim 30, Guo teaches PEG and PLGA being dissolved to get a solution (Para 0086) indicating the solubility of PEG. Furthermore, in paragraph 0036, it states inserting delivery system will come in contact with water or other physiological fluid that enter the system and contacts the inner core (including PEG within the inner core), and it is known that PEG is soluble in water, which meets the claimed limitation of PEG being soluble.
The teachings of Guo have been set forth above.
Guo does not teach explicitly the amount of polyethylene glycol in the delivery system as recited in the instant claims. Guo also does not explicitly teach specifically the liquid phase comprising a specific amount of protein such as the amount of VEGF antagonist (a protein) recited in instant claims. Guo does not expressly teach the protein present in a solid phase with PEG and wherein the protein is retained as a lyophilized protein or spray dried protein. Further, Guo does not explicitly teach the precipitator excipient (PEG) concentration is used to control the solubility of the protein. Guo also does not teach the protein having at least 80% native conformation, structure or function in the liquid phase (i.e., stable). However, these deficiencies are cured by Herrmann.
Herrmann throughout the reference teaches addition of polyethylene glycol in delivery system affects the protein release kinetics and stability (Pg. 1527, Purpose) and that sustained release system for pharmaceutical proteins are highly desirable to reduce administration frequency and enhance their in vivo stability (Pg. 1527, Intro). Herrmann teaches the device disclosed provide complete protein release in its native form and the protein release patterns can be adjusted by addition of PEG (Introduction). Herrmann teaches IFN-alpha (protein) bulk solutions were precipitated with 5-20% PEG (Pg. 1529, Col. 2, Fluorescence Spectroscopy, line 2-3). The device was filled with lyophilized IFN-alpha protein and PEG containing pellets (i.e., protein in solid phase) (Pg. 1529, col. 2, Macropore Release Model). Precipitation offers the benefit of protein stabilization during fabrication process of controlled release devices. Herrmann teaches only non-precipitated protein (i.e., solubilized or liquid phase) diffuses out of the system. (page 1532).
Herrmann teaches IFN-alpha (protein) bulk solutions were precipitated with 5-20% PEG (Pg. 1529, Col. 2, Fluorescence Spectroscopy, line 2-3). Through straightforward calculation, this equates to 50 mg/ml to 200 mg/ml concentration of PEG, which overlaps the instantly claimed amount.
With respect to the claimed limitations wherein liquid phase comprises the recited amount of VEGF antagonist (a protein), Herrmann teaches IFN-alpha bulk solutions are precipitated with 5-20% PEG and re-dissolved in excess of buffer to final protein concentration of 0.05 mg/ml (Pg. 1529, Col. 2, Fluorescence Spectroscopy, line 2-5). This entirely overlaps the protein concentration in liquid phase recited in instant claims.
With respect to the VEGF antagonist (a protein) having at least 80% native conformation, structure or function in the liquid phase (i.e., stable), Herrmann teaches IFN-alpha protein precipitation with polyethylene glycol and re-dissolution revealed a complete protein recovery with PEG concentration 4-20%. Moreover, no chemical degradation such as oxidation occurred, since the amount of oxidized IFN-a detected by RP-HPLC in standard solutions as well as in the solutions of re-constituted IFN-a was less than 2%. Furthermore, size exclusion chromatography and SDS gel electrophoresis were used to detect protein aggregation and fragmentation, which indicated no significant differences in protein quality before and after precipitation and dissolution (Pg. 1533, Col. 1, Effects of IFN-alpha precipitation and re-dissolution on protein stability). This teaching of Herrmann reads on the protein retaining native conformation, structure or function in the liquid phase (i.e., solubilized form). Further, Herrmann teaches that the presented sustained release matrix composition offer two major benefits via its in-situ precipitation mechanism. First the reversible precipitation of IFN-alpha in PEG containing lipidic implants facilitates the sustained protein release with nearly constant release rates and a low burst effect. Moreover, the precipitation also ensures low protein concentrations within the implant pores and therefore the tendency of protein aggregation is reduced (see: Pg. 1536, left Column, Second Paragraph).
With respect to the claimed limitation wherein the precipitator excipient (PEG) concentration is used to control the solubility of the VEGF antagonist (a protein), Herrmann teaches the solubility of protein was experimentally determined in differently concentrated aqueous PEG solutions and that the solubility of IFN-alpha is strongly affected by the presence of PEG. Guo further states that 10% PEG resulted in an almost negligible protein solubility (0.02 mg/ml) (Pg. 1531, Col.1, Solubility Studies). Furthermore, Herrmann teaches that the concentration of the supernatant is in equilibrium with the precipitated/crystalline phase (Pg. 1528-1529, Solubility Studies).
The teachings of Guo and Herrmann have been set forth above.
The references above do not explicitly teach the protein is receptor-Fc-fusion protein (i.e., aflibercept (i.e., VEGF antagonist)) and that the formulation releases the amount recited in instant claims when administered into the vitreous humor. However, these deficiencies are cured by de Juan, JR.
Juan teaches an implantable therapeutic device to release a therapeutic agent and the device is implanted into the vitreous humor of the eye (Abstract; Para 0014). The therapeutic device is configured to provide continuous release of therapeutic quantities of at least one therapeutic agent for an extended time of at least 3 months to reduce frequency of injection and risk of infection (Para 0015). The reference teaches aflibercept as one of the therapeutic agent (Page 65, Table 1A). Juan teaches the therapeutic device to release a therapeutic agent comprises a reservoir coupled to a porous structure. The reservoir comprises a volume sized to receive and release therapeutic amounts of the therapeutic agent. The volume of the reservoir and release rate of the porous structure can be tuned. The therapeutic device has a chamber volume sized to store a certain amount of the drug. (abstract; 0018; 0019; 0033; 0045).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Guo to incorporate the teachings of Herrmann and Juan and specifically include the claimed concentration of polyethylene glycol. One would be motivated to do so because Herrmann throughout the reference teaches that presence of polyethylene glycol with IFN-alpha protein facilitates the sustained protein release with nearly constant release rates and moreover, the protein aggregation is reduced (Pg. 1536, Col 1, Para 2). One would be motivated to incorporate the PEG concentration Herrmann teaches to achieve similarly desired results because both Guo and Herrmann are directed to sustained release drug delivery systems. Furthermore, since both Guo and Hermann teach a composition with protein and PEG, one would necessarily achieve similar results of protein stability in physiological environment and the protein being in equilibrium in the solid and liquid phase, in particular because Herrmann teaches that the concentration of the supernatant is in equilibrium with the precipitated/crystalline phase.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Guo to incorporate the teachings of Herrmann and Juan and specifically include a protein concentration of 0.05 mg/ml in the liquid phase. One would be motivated to do so because Herrmann throughout the reference teaches that presence of polyethylene glycol with IFN-alpha protein facilitates the sustained protein release with nearly constant release rates and moreover, the protein aggregation is reduced (Pg. 1536, Col 1, Para 2). Thus, comprising similar amount of protein concentration in the liquid phase would yield predictable results of stable protein delivery and lower protein aggregation. Further, as discussed supra, Herrmann discloses the ability of PEG to precipitate protein and teaches the solubility of IFN-alpha protein is strongly affected by the presence of PEG. Herrmann teaches solubility fraction decreases non-linearly with increasing PEG concentration (see: Solubility Studies). Figure 2 of instant specification also discloses protein solubility decreasing with increasing PEG concentration. Instant specification in paragraph 33 disclose that biphasic system includes drug which exists in two phases which includes an insoluble (precipitated) or solid phase, and a soluble or liquid phase. Thus, even though the Guo reference does not expressly teach the protein present in both a liquid phase and in a solid phase, the Herrmann reference teaches an overlapping amount of PEG and thus an overlapping amount of PEG would necessarily result in the protein being in a solid phase (precipitated) and a soluble (liquid phase).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Guo to incorporate the teachings of Herrmann and Juan with respect to the protein stability. One would have been motivated to do so because Herrmann teaches that protein precipitation with polyethylene glycol and re-dissolution revealed a complete protein recovery and that the sustained release matrix composition offers major benefits via its precipitation mechanism as discussed above. The reference provides motivation for why precipitation would be desired in the sustained release formulation and that complete protein recovery is achieved via this mechanism and therefore one would have been motivated to utilize this teaching of the reference along with the concentrations of the protein and polyethylene glycol components taught by the reference and discussed above.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Guo to incorporate the teaching of Herrmann and Juan and include a concentration of PEG as taught by Herrmann and manipulate the amount during routine experimentation to identify and optimize the most desirable concentration that would yield predictable protein solubility and stability along with the desired release rate.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Guo to incorporate the teachings of Herrmann and Juan and include aflibercept as the protein in the formulation. Both Guo and Herrmann teach the inclusion of a protein in an implantable sustained release formulations. Herrmann teaches that the release of pharmaceutical proteins can be controlled by an in-situ precipitation (Page 1527, Abstract). Even though the references do not explicitly disclose aflibercept, they teach proteins in general and therefore one would have been motivated to include a protein based on the treatment that is desired. Juan teaches aflibercept as a therapeutic agent in an implantable sustained released formulation for the treatment of eye and it would have been obvious to one of ordinary skill in the art to incorporate aflibercept into the teachings of Guo and Herrmann if treatment of eye was desired.
It would have been prima facie obvious to one of ordinary skill in the art to have the formulation release a specific amount of aflibercept (VEGF antagonist) based on the amount necessary for the treatment of a condition. The duration and dosage of a drug is patient specific and based on the condition being treated and therefore it would have been obvious to have the formulation release an amount recited in the instant claims. Furthermore, the Guo reference teaches that the release rate of the active agent can be controlled by the size of the diffusion pores and the permeability of the second layer of the polymer system (see Para 0008 and 0037). Therefore, it would have been obvious to one of ordinary skill in the art to manipulate the release rate of aflibercept by varying the size of the diffusion pores or the permeability of the second layer of the polymer system based on the desired therapeutic dose.
It would have also been obvious to one of ordinary skill in the art to vary the concentration of PEG and protein (i.e., VEGF antagonist) in different components (as recited in instant claim 30) so to optimize the desired results (e.g., release rate) and obtain stable release of the agent/protein because, as discussed supra, Herrmann throughout the reference teaches addition of polyethylene glycol in delivery system affects the protein release kinetics and stability and that solubility of IFN-alpha is strongly affected by the presence of PEG.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Guo to incorporate the teachings of Herrmann and Juan and have the VEGF antagonist protein present in a solid phase with PEG and wherein the protein is retained as a lyophilized protein or spray dried protein. As discussed supra, Herrmann teaches the device disclosed provide complete protein release in its native form and the protein release patterns can be adjusted by addition of PEG (Introduction). Herrmann teaches IFN-alpha (protein) bulk solutions were precipitated with 5-20% PEG (Pg. 1529, Col. 2, Fluorescence Spectroscopy, line 2-3). The device was filled with lyophilized IFN-alpha protein and PEG containing pellets (i.e., protein in solid phase) (Pg. 1529, col. 2, Macropore Release Model). Precipitation offers the benefit of protein stabilization during fabrication process of controlled release devices. Herrmann teaches only non-precipitated protein (i.e., solubilized or liquid phase) diffuses out of the system. (page 1532). Thus, one skilled in the art would have been strongly motivated to have the protein present in a solid phase with PEG as a lyophilized protein to achieve the sustained release and stability of the protein as taught in Herrmann.
With respect to the instantly claimed recitation wherein the semi-permeable membrane permits diffusion of the VEGF-antagonist in the liquid phase from inside of the semi-permeable membrane to an outside aqueous environment while preventing the VEGF-antagonist in the solid phase from diffusing out, Guo teaches the release rate of the agent may be controlled by size of the diffusion pores, the permeability of the second layer of the polymer system, the physical properties of the core (e.g., the permeability or solubility of an agent in the biocompatible solid as opposed to the permeability or solubility of the agent in the biocompatible fluid of the biocompatible core component) (Para 0037). Guo also discloses the solubility of the agent in the core impacts the rate of release of the agent from the polymer system and the agent’s release rate from the polymer core where an agent is soluble in the core exceeds the rate of release where the agent is only slightly or very slightly soluble in the polymer core (Para 0048). It would have been obvious to one skilled in the art to manipulate the permeability and size of the diffusion pores to allow only the solubilized (i.e., liquid) protein agent and retain the insoluble (solid) protein agent, particularly because Guo teaches soluble agents release rate exceeds that of insoluble agent as stated above. Further, as discussed supra, Herrmann teaches only non-precipitated protein (i.e., solubilized or liquid phase) diffuses out of the system. (page 1532). Thus, having the protein as a lyophilized protein (solid phase) would only allow diffusion of solubilized form and not the solid form of the protein.
With respect to the instantly claimed recitation wherein the precipitator excipient (PEG) causes VEGF antagonist protein to precipitate from liquid phase to solid phase, as discussed supra, Guo teaches the biocompatible fluid component can be comprised of polyethylene glycol (Pg. 8, claim 45, line 1-2) and Herrmann teaches protein solutions precipitate in presence of PEG (Pg. 1529, Col. 2, Fluorescence Spectroscopy, line 2-3). Thus, presence of PEG in the fluid component would cause protein to precipitate.
With respect to the instantly claimed recitation “wherein the biphasic pharmaceutical composition is contained in a reservoir device with a porous structure having a volume between about 5 μl and about 150 μl containing between about 5 mg to about 180 mg of the VEGF-antagonist”, the instant claims are direct to a biphasic pharmaceutical formulation and the recitation above is an intended use of the biphasic pharmaceutical formulation. The prior art teaching the same biphasic pharmaceutical formulation would necessarily be capable of being contained in a reservoir device recited in the claims. Further, the instant specification disclose the biphasic formulation separate from the reservoir device wherein a reservoir device is used to house/contain the biphasic formulation (para 0029-0048), which also suggests that the biphasic pharmaceutical formulation contained in a reservoir device is an intended use of the biphasic pharmaceutical formulation.
In the instant that the biphasic pharmaceutical composition contained in a reservoir device with porous structure is a necessary part of the biphasic pharmaceutical formulation, Guo teaches the invention provides a polymer drug delivery system comprising an inner core or reservoir that contains a therapeutically effective amount of an agent. The drug delivery system comprises a first coating layer, surrounding the inner core, that is impermeable, negligibly or partially permeable to the agent and, optionally, a second coating layer that is permeable or semi-permeable to the agent and contain diffusion pores that allow the drug to diffuse from the core out of the system (Para 0005 and 0008). Thus, Guo already teaches a delivery device with a reservoir and porous structure, wherein the reservoir contains the pharmaceutical composition comprising the active agent. Juan also teaches the therapeutic device to release a therapeutic agent comprises a reservoir coupled to a porous structure. The reservoir comprises a volume sized to receive and release therapeutic amounts of the therapeutic agent. The volume of the reservoir and release rate of the porous structure can be tuned. The therapeutic device has a chamber volume sized to store a certain amount of the drug. (abstract; 0018; 0019; 0033; 0045). Therefore, based on the teachings of Guo and Juan, it would have been obvious to one skilled in the art to contain the composition in a reservoir device with a porous structure having a volume between about 5 μl and about 150 μl containing between about 5 mg to about 180 mg of the protein because Juan teaches the volume of the reservoir and release rate of the porous structure can be tuned and the therapeutic device has a chamber volume sized to store a certain amount of the drug. One skilled in the art would have found it obvious to determine the optimal volume and amount of drug/protein needed based on parameters such as type of disease being treated and dose indicated for that disease, which can be based on patient size, age, etc.
Regarding an open biphasic pharmaceutical formulation, paragraph 31 of specification states an example of an open system is a device with porous walls that allows the soluble form of the protein to have access to the outside environment. As discussed supra, the prior art also teaches porous walls that allow substances to have access to the outside environment. Thus, the cited prior art above teaches an open biphasic pharmaceutical formulation.
With respect to the claimed recitation wherein the semi-permeable membrane preferentially retains PEG while allowing diffusion of protein, as discussed supra, the examiner interprets that the claims do not require that the semi-permeable membrane preferentially retains PEG while allowing diffusion of protein and that this limitation is optional. Further, as discussed in the 112 rejection above, the instant specification do not disclose or describe what membrane is impermeable to PEG but allows diffusion of protein and the specification also do not describe how the pores allow the diffusion of the protein but not PEG. The Guo reference, as discussed supra, teaches that the drug delivery system comprises a first coating layer, surrounding the inner core, that is impermeable, negligibly or partially permeable to the agent and, optionally, a second coating layer that is permeable or semi-permeable to the agent and contain diffusion pores that allow the drug to diffuse from the core out of the system (Para 0005 and 0008). The Guo reference teaches structurally the same formulation as instantly claimed wherein coating layer surrounds the inner core (comprising solid and liquid phase) and the coating layers having pores that allow the drug to diffuse out. Thus, a similar structure of the formulation taught by Guo would necessarily result in similar diffusion pattern of PEG.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 51, 53 and 55 are rejected under 35 U.S.C. 103 as being unpatentable over Guo (US 2014/0363482; Dec. 11, 2014) in view of Herrmann (Pharmaceutical Research, Vol. 24, No. 8, Pg. 1527-1537; August 2007) and de Juan, JR. et al. (US 2012/0095439 A1; Apr. 19, 2012) as applied to claims 1, 8, 9, 29, 30, 31, 33-34, 38-39, 45-49 and 65-67 above and further in view of Desai (ACS Nano. 2015 June 23, 9(6): 5675-5682).
The teachings of Guo and Herrmann have been set forth above.
The above cited references do not teach the semi-permeable membrane comprises nanoporous polycaprolactone or microporous caprolactone. However, Desai cures this deficiency.
Desai throughout the reference discloses micro and nanoporous polycaprolactone membranes which are protected from immune responses and elicit minimal foreign body response. Desai teaches these membranes allow for diffusion with flexibility and precise membrane control. (see: Abstract; Results and Discussion).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the above references to incorporate the teachings of Desai and include specifically a micro or nanoporous polycaprolactone membrane as the semi-permeable membrane taught in Guo. As discussed supra, Guo already teaches including a semi-permeable membrane and Desai teaches micro and nanoporous polycaprolactone membranes which are protected from immune responses and elicit minimal foreign body response. Desai teaches these membranes allow for diffusion with flexibility and precise membrane control. Since Guo also teaches device which is implanted in the physiological system, one skilled in the art would have strongly been motivated to use the micro or nanoporous polycaprolactone membrane of Desai as the semi-permeable membrane.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 52, 54 and 56 are rejected under 35 U.S.C. 103 as being unpatentable over Guo (US 2014/0363482; Dec. 11, 2014) in view of Herrmann (Pharmaceutical Research, Vol. 24, No. 8, Pg. 1527-1537; August 2007) and de Juan, JR. et al. (US 2012/0095439 A1; Apr. 19, 2012) as applied to claims 1, 8, 9, 29, 30, 31, 33-34, 38-39, 45-49 and 65-67 above and further in view of Kloxin (Chem. Soc. Rev. 2013, 42, 7335-7372).
The teachings of Guo and Herrmann have been set forth above.
The above cited references do not teach the semi-permeable membrane comprises a crosslinked hydrogel. However, Kloxin cures this deficiency.
Kloxin teaches degradable and cell-compatible crosslinked hydrogels can be designed to mimic the physical and biochemical characteristics of native environment and provide tunability of degradation rates and related properties such as permeability under physiological conditions. Such hydrogels find widespread application including controlled bioactive molecule delivery. (see: abstract; entire document).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the above references to incorporate the teachings of Kloxin and include specifically a crosslinked hydrogel as the semi-permeable membrane taught in Guo. As discussed supra, Guo already teaches including a semi-permeable membrane and Kloxin teaches degradable and cell-compatible crosslinked hydrogels can be designed to mimic the physical and biochemical characteristics of native environment and provide tunability of degradation rates and related properties such as permeability under physiological conditions. Such hydrogels find widespread application including controlled bioactive molecule delivery. Since Guo also teaches device which is implanted in the physiological system for sustained delivery, one skilled in the art would have strongly been motivated to use the crosslinked hydrogel of Kloxin as the semi-permeable membrane.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Response to Arguments
Applicant's arguments filed, 3/31/2026, with respect to the 103 rejections have been fully considered but they are not persuasive.
Applicant in the remarks state that the primary references cited by the examiner are Guo and Herrman. Applicant have distinguished these references previously and have added the term “open” to the claims to support differences between the claims and the cited prior art.
In response, regarding an open biphasic pharmaceutical formulation, paragraph 31 of specification states an example of an open system is a device with porous walls that allows the soluble form of the protein to have access to the outside environment. As discussed supra, the prior art also teaches porous walls that allow substances to have access to the outside environment. Thus, the cited prior art above teaches an open biphasic pharmaceutical formulation.
Applicant argued that in Herrmann, the solubility of IFN-alpha within the water filled pores increases continuously due to the leaching of PEG out of the system. However, in the present invention, the PEG does not leach out of the system.
In response, firstly it is argued that the instant claims do not require that PEG is retained in the
biphasic system because the claims recite the semi-permeable membrane preferentially retains PEG. Thus, applicant's argument that Herrmann's implant leached PEG from the implant is
not persuasive because the instant claims do not require that PEG cannot be released out from the
biphasic system. Further, as discussed supra, the prior art (Herrmann) teaches that in PEG containing devices the solubility of the protein increases continuously due to the leaching of PEG out of the system. Herrmann teaches that PEG cause the precipitation of the protein and increasing PEG concentration reduces the solubility of the protein. Herrmann teaches that only non-precipitated protein (solubilized) is diffused out of the matrix. As the PEG leaches out of the system, the PEG concentration decreases and more protein is solubilized, thereby leading to release of the solubilized protein out of the system (see: Herrmann: solubility studies). The instant application also discloses inclusion of PEG for precipitating the protein and it is unclear how the instant formulation is able to release the protein while retaining PEG with the protein in the solid phase.
Applicant argued Juan does not disclose the use of PEG in a solid precipitate with the protein to achieve equilibrium. Similar arguments were made regarding Desai and Kloxin not teaching the use of PEG in open biphasic pharmaceutical formulation.
In response to applicant's arguments against the reference individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). As discussed supra, Both Guo and Herrmann teach the inclusion of a protein in an implantable sustained release formulations. Herrmann teaches that the release of pharmaceutical proteins can be controlled by an in-situ precipitation (Page 1527, Abstract). Even though the references do not explicitly disclose aflibercept, they teach proteins in general and therefore one would have been motivated to include a protein based on the treatment that is desired. Juan teaches aflibercept as a therapeutic agent in an implantable sustained released formulation for the treatment of eye and it would have been obvious to one of ordinary skill in the art to incorporate aflibercept into the teachings of Guo and Herrmann if treatment of eye was desired.
Regarding Desai, Guo already teaches including a semi-permeable membrane and Desai teaches micro and nanoporous polycaprolactone membranes which are protected from immune responses and elicit minimal foreign body response. Desai teaches these membranes allow for diffusion with flexibility and precise membrane control. Since Guo also teaches device which is implanted in the physiological system, one skilled in the art would have strongly been motivated to use the micro or nanoporous
polycaprolactone membrane of Desai as the semi-permeable membrane.
Regarding Kloxin, Guo already teaches including a semi-permeable membrane and Kloxin teaches degradable and cell-compatible crosslinked hydrogels can be designed to mimic the physical and biochemical characteristics of native environment and provide tunability of degradation rates and related properties such as permeability under physiological conditions. Such hydrogels find widespread application including controlled bioactive molecule delivery. Since Guo also teaches device which is implanted in the physiological system for sustained delivery, one skilled in the art would have strongly been motivated to use the crosslinked hydrogel of Kloxin as the semi-permeable membrane.
Conclusion
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/ALI S SAEED/Examiner, Art Unit 1616
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