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 .
Summary
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 09/08/2025 has been entered.
Receipt of Applicants’ Amendments and Remarks filed on 09/08/2025 are acknowledged.
Claims 1-2,17,19-23, 25-26, 28-35 and 37 are pending.
Claims 3-16, 18, 24, 27, and 36 are cancelled.
Claims 1, 17, 20-23, 25, 26, 28 are amended.
Claims 1-2,17,19-23, 25-26, 28-35 and 37 are pending and are included in the prosecution.
Priority
Instant application 17/281,902 filed claims benefit as follow: This application is a 371 of PCT/NL2019/050660 filed 10/02/2019, which in turn claims priority to
PCT/ NL2019/050660 which has PRO 62/740,145 filed 10/02/2018.
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.
Claim 32 and 37 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.
Claim 32 recites “microspheres releases less than about 20% of hCG” and is inconsistent with amended claim 1 of microsphere releases less than 1/7 of hCG. Thus, the 20% is inconsistent with the 1/7. Appropriate correction is required.
Claim 37 recites “the method causes extended release”. Examiner note that the method does not cause extended release what so ever, it is the properties that is in the composition that causes the extended release. 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.
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 1-2,17,19-23, 25-26, 28-35 and 37 are rejected under 35 U.S.C. 103 as being unpatentable over Steendam et al. (US 2014/0199385 A1) hereinafter reference is referred as Steendam in view of Prasad et al. (WO 2012110886 A1) hereinafter reference is referred as Prasad in view of Kacker et al. (US 20180214507 A1) hereinafter reference is referred Kacker (both references are cited in IDS filed on 03/31/2021), and further in view of Microspheres for protein delivery prepared from amphiphilic multiblock copolymers (hereinafter the article is referred as Zhou).
Steendam teaches (in abstract) a biodegradable, semi-crystalline, phase separated thermoplastic multi-block copolymer, a process for preparing said multi-block copolymer, a composition for the delivery of at least one biological active compound, and to a method for delivering a biologically active compound to a subject in need thereof. A multi-block copolymer of the invention is characterized in that:
a) it comprises at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment,
b) said multi-block copolymer having a T g of 37° C. or less and a 110-250° C. under physiological conditions;
c) the segments are linked by a multifunctional chain-extender;
d) the segments are randomly distributed over the polymer chain;
e) at least part of the pre-polymer (A) segment is derived from a water-soluble polymer.
Regarding claim 1, Steendam teaches the subject matter of instant multi-block copolymer comprising thermoplastic multi-block copolymer (¶ 0016) comprising at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment (¶ 0017-0018), wherein the segments are linked by a multifunctional chain-extender (¶ 0019), wherein the segments are randomly distributed over the polymer chain (¶ 0020), wherein at least part of pre-polymer (A) is derived from a water-soluble polymer (¶ 0021) and is polyethylene glycol (PEG) (¶ 0061); wherein the triblock copolymers comprising microspheres composed of poly(L-lactic-co-glycolic acid)-poly( ethylene glycol)-poly(lactic-co-glycolic acid) and poly(L-lactic acid)-poly( ethylene glycol)-poly(L-lactic acid) copolymers (¶ 0007), and under physiological conditions of T g of 37° C or less and when poly(dioxanone) (PDS) is used as segment B, multi-block copolymers with a Tm of 80-90° C, when poly(ε-caprolactone) (PCL) Tm of 40-60° C (¶ 0037-0038). Therefore, the limitation of amended claim to specify pre-polymer (A) polyethylene glycol as the water-soluble polymer and the linear architecture of the multi-block copolymer (entire ref) is taught.
Prasad teaches a controlled-release formulation comprising human chorionic gonadotropin (hCG) or hCG variants, a process of preparation and use of the formulation, wherein the formulation avoids the need for repeated injections (abstract). Furthermore, Prasad teaches human chorionic gonadotropin (hCG) or hCG variants, a process of preparation and use of the formulation, wherein the formulation is directed to water-soluble polymer selected from the group consisting of polyethylene glycol (PEG) (page 5, line 15-17) and a controlled release formulation comprising biodegradable non-toxic FDA approved polymers nano-systems are an attractive alternative to liposomes since they have the advantages of longer circulation in the blood stream and generally higher drug carrying capacity, along with polymers, for example, poly (lactic acid) (PLA), poly (lactic co-glycolic acid) (PLGA) have been extensively investigated for their biocompatibility and potential capability of releasing therapeutically proteins in a controlled way even over a prolonged period of time (page 4, lines 13-18), coupled with human chorionic gonadotropin (hCG) or hCG variant loaded in microspheres (page 6, lines 5-7) and smart bio-degradable polymers and/or nanoparticle protein absorption, bioconjugation, and encapsulation are excellent alternatives for ensuring that the structure–activity relationship (SAR) of proteins from natural sources such as hCG that are not degraded during the course of administration by parenteral routes (page 5, lines 21-24). Furthermore, Prasad teaches microspheres facilitates controlled and sustained release (page 15, line 1) and the formulation could be administered as a depot injection containing the active drug embedded in the nanoparticles (nanospheres, nano-capsules, and nano particles) (page 15, lines 4-6). Notably, Prasad disclose prior art teaches protein delivery systems is often characterized by low entrapment efficiency, decrease burst release, instability of encapsulated hydrophilic protein and partial protein release and to improve performance of these polymer nanoparticles, polysaccharides, for example as alginate (ALG) and chitosan (CS) could be applied, CS and its derivatives have been intensively studied as carriers for proteins and drugs (page 4, lines 23-28). Prasad further disclose the controlled-release formulation comprising hCG is stable effective and advantageous over the hCG formulation known in the art, containing multiple uses to include therapy for increasing the levels of hCG in maintenance of pregnancy, taking care of the needs of a stable and preserved solutions, formulations, and products comprising of hCG or hCG variants and using these product in the field of gynecology (page 8, lines 1-6) and polymeric nano/microparticles offer specific advantages over liposomes or other carrier by increasing the stability of the drug and its variants, and possess useful controlled release properties, wherein the particle size varies from 10 to 1000 nm, and the hCG loaded microsphere is prepared by dissolving, entrapping, encapsulating or attached to polymer matrix and depending on the method of preparation microparticles, microspheres, nanoparticles, nanospheres or nano-capsules or a combination of all can be obtained (page 8, lines 15-21).
Regarding claims 1 and 37, as noted above, Prasad teaches hCG, biodegradable polymer microspheres and controlled-release formulation.
Regarding claims 1, 2 and 32, Prasad teaches a controlled release hCG formulation, wherein the formulation exhibits in-vitro rate of release of hCG or hCG variant in the range of 1000 IU (International Units) to 8000 IU withing 24 hours. of administration and 10 IU to 1000 IU per 24 hours. for remaining period (claim 13) and wherein in-vivo rate of release is in the range of 0.1 IU/ml to 3.0 IU/ml of plasma within 24 hours of administration and 0.0002 IU/ml to 0.21 IU/ml of plasma for remaining period (claim 14). Furthermore, Prasad disclose the addition of sodium chloride (NaCl) to the hCG loaded microsphere drastically reduced the burst release from 90% to 43% (Example 4) and the decrease in the initial burst release of hCG in presence of NaCl is because of a denser structure of the resulting microsphere (page 19, lines 20). Thus, the reduction of the burst release rate above, would reasonably result in a controlled-release rate of hCG content of the microsphere in the range of 10% to 57%. Therefore, the limitation and structural features overlaps instant release range of 3% to about 40%, and would reasonably overlaps with the amended 1/7 of hCG content of the microspheres within about the first 24 hours.
Regarding claim 30, Prasad teaches a controlled release hCG formulation that releases hCG or hCG variant for at least 15 days or more (page 13, lines 1-20 and claims 12 and 15).
Regarding claim 31, Prasad teaches encapsulated hCG molecule, wherein the formulation is with or without excipient (page 9, lines 19-21), active drug along with excipients (page 15, line 9), and PLA and PLGA are FDA-approved as excipients to achieve sustained release of the active ingredient (page 4, lines 22-23).
Regarding claim 33, Prasad teaches administration is intramuscular or subcutaneous injections (page 15, line 10).
Regarding claims 34-35, Prasad teaches a method of treating a subject in need of hCG comprising the microsphere controlled release formulation for fertility treatment (page 2, line 9) in ovulation induction (page 5, line 27).
Prasad fails to specifically teach [poly(ε-caprolactone)-co-polyethylene glycol-co-poly(ε-caprolactone)]-b-[poly(p-dioxanone)] multi-block copolymer and polybutylene terephthalate (PBT).
Kacker teaches microspheres formulation (paragraphs 0014, claims 42, 45, and 49) comprising gonadotropin-releasing hormone (GnRH) also known as luteinizing hormone releasing hormone (LHRH), controls the secretion of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH) from the anterior pituitary gland, wherein analogues of GnRH are currently used to treat many medical conditions that require manipulation of the production of the sex hormones, testosterone and estrogen (paragraph 0003). In another aspect of the composition, Kacker disclose a therapeutically effective amount of a GnRH antagonist in combination with a multi-block copolymer, wherein said multi-block copolymer comprises randomly or non-alternatingly arranged hydrolysable segments, wherein each segment comprises pre-polymer A or pre-polymer B, and wherein said segments are operably linked to each other by a multifunctional chain extender, and in an exemplary embodiment, the multi-block copolymer is a phase separated multiblock copolymer comprising one or more segments of a linear soft biodegradable pre-polymer A having a glass transition temperature (Tg) lower than 37 °C, and one or more segments of a linear hard biodegradable pre-polymer B having a melting point temperature (Tm) of 40-100 °C (paragraph 0010) wherein the biodegradable multiblock copolymers comprising therapeutically effective amount of a GnRH antagonist in combination with poly(ε-caprolactone) (PCL) (paragraph 0007), poly-ethylene-glycol (PEG) (paragraph 0007), poly(L-lactide) or a combination thereof (paragraph 0006). Furthermore, Kacker discloses polyether is polyethylene glycol (PEG), poly-propylene-glycol (PPG) and combinations thereof (paragraph 0081, claim 62).
Regarding claim 1, as noted above, Kacker teaches biodegradable multiblock copolymers, phase separated multi-block copolymers (also in claim 63), a biodegradable thermoplastic polyester (paragraph 0008) with hydrolysable segments.
Regarding claims 17 and 19, as noted above, Kacker teaches temperature (Tg) lower than 37 °C and melting point temperature (Tm) of 40-100 °C, and therefore overlaps with instant range of multi-block copolymer (Tg) of 37 °C or less and a Tm of 50-110 °C; a multifunctional chain extender and randomly distributed segments are taught. Additionally, Kacker teaches dioxanone (paragraphs 0007, 0044, 0074, claims 11, 60 and 61) and pre-polymers A or B comprise a hydrolysable polyester, poly ether ester, polycarbonate, polyester carbonate, polyanhydride or copolymers thereof, derived from cyclic monomers of lactide (L, D or L/D), 1, 4-dioxane-2-one (para-dioxanone) (paragraph 0074, claim 60) and pre-polymers A and B are selected in such a way that the segments would exhibit significantly different properties, for example, but not limited to thermal, degradation and hydrophilic properties (paragraph 0073), characteristics of microspheres may be altered during preparation by manipulating the water soluble polymer concentration, reaction temperature, pH, concentration of therapeutic agent (paragraph 0096) and the amount of pre-polymer in the composition can be any suitable amount, known to one skilled in the art, wherein the amount may be of about 10-90 wt % (paragraph 0084).
Regarding claims 20 and 21, Kacker teaches in one embodiment, each pre-polymers A and B has a number average molecular weight between 300 and 30,000 (paragraph 0081). Therefore, overlaps with instant molecular weight range of about 1300 to about 10080 g/mol.(paragraph 0050), for example, the suitable biodegradable polymer is 50:50 DL-lactide co-glycolide having a carboxy terminal group or is 75:25 poly (DL-lactide-co-glycolide) with a carboxy terminal group that is protected, and other suitable copolymers known to one of skilled in art can also be used (paragraph 0049) which reads on substituting for PEG and PBT.
Regarding claims 22 and 23, Kacker teaches multi-block copolymer is a phase separated multiblock copolymer comprising one or more segments of a linear soft biodegradable pre-polymer A having a glass transition temperature (Tg) lower than 37°C and one or more segments of a linear hard biodegradable pre-polymer B having a melting point temperature (Tm) of 40-100°C) (paragraph 0010). A person having ordinary skill in the art (PHOSITA) would be able to select a pre-polymer B having an additional parameter of Tg of less than about 0 °C.
Regarding claim 25, Kacker teaches chain-extender can be any suitable multifunctional chain extender, known to one of skilled in the art, and the pre-polymers are linked by di-functional chain-extender, and example includes but not limited to, a di-isocyanate chain-extender (paragraph 0083).
Regarding claim 26, Kacker teaches pre-polymer comprises at least two different cyclic monomers (paragraph 0079) and examples of non-cyclic initiator include but not limited to, succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, glycolic acid, hydroxybutyric acid, ethylene glycol, diethylene glycol, 1,4-butanediol and/or 1,6-hexanediol (para. 0080), and wherein cyclic monomers examples are glycolide, lactide, (L, D or DL), ε-caprolactone, 1\-valerolactone, trimethylene carbonate, tetramethylene
carbonate, 1,4-dioxane-2-one (para-dioxanone ), 1,5-dioxepane-2-one and cyclic anhydrides (paragraph 0078).
Zhou teaches poly(ε-caprolactone)-poly(ethylene glycol) copolymers in microspheres directed as carriers and that these matrix polymers may be optimized as carriers in the protein (antigen) delivery system for different purposes (abstract).
Regarding claims 28 and 29, Zhou teaches multiblock copolymers, triblock copolymers comprising poly(ε-caprolactone)-poly(ethylene glycol) copolymers in microspheres (abstract) and ABA-type block copolymers (PELA) comprising poly(D,L-lactide) and (A) poly(ethylene glycol) (B) segments obtained by ring-opening polymerization, wherein the second component PEG was widely used to improve the biocompatibility of the blood contacting materials (page 3563, right column, paragraph 1).
Claims 1-2,17,19-23, 25-26, 28-35 and 37 are rejected under Steendam in view of Prasad Kacker and further in view of Zhou does not teach within a single embodiment in order to anticipate but renders obvious the instant claims. As such it would be obvious at the time the invention was filed to rearrange the components of an extended release hCG composition with the biodegradable multi-block copolymers comprising at least one amorphous hydrolysable pre-polymer A segment and at least one semi-crystalline hydrolysable pre-polymer B segment and obtain a composition as claimed. A reference is analyzed using its broadest teachings. MPEP 2123 [R-5]. Where, as here, the specific combination of features claimed is disclosed within the broad teachings of the reference but the reference does not disclose the specific combination of variables (for example, the biodegradable multi-block copolymer [poly(ε-caprolactone)-co-polyethylene glycol-co-poly(ε-caprolactone)]-b-[poly(p-dioxanone)] under physiological conditions of a desired glass transition temperature (Tg) and melting point (Tm) of claims 22, and 23, and different average molecular weight of pre-polymer B in claims 20-21, in a specific embodiment or in a working example, “picking and choosing” within several variables does not necessarily give rise to anticipation. Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989).
However, "when 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 v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that "[a] person of ordinary skill is ... a person of ordinary creativity, not an automaton." Id. at 1742.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to rearrange the disclosed elements and embodiments of Steendam in view of Prasad, Kacker and further in view of Zhou, to include an example biodegradable multi-block copolymers ([poly(ε-caprolactone)-co-polyethylene glycol-co-poly(ε-caprolactone)]-b-[poly(p-dioxanone)]), water-soluble polymers, multifunctional chain extender, pre-polymer A and pre-polymer B average molecular weights and the physiologic conditions of ( Tg ) and (Tm ), to prepare the claimed composition. Such a rearrangement by a person of ordinary skill in the art who is not an automaton to yield the instantly claimed compositions and methods is within the purview of the ordinary skilled artisan upon reading Steendam, Prasad, Kacker and further in view of Zhou, as cited above, and would yield predictable results.
Response to Remarks/Amendments
Applicant asserts the cited reference Prasad teaches away from claims by showing that PLGA is capable of producing extended release of hCG and that burst release of hCG is obtained in the PLGA-based microspheres, and that Lu relates to graft polymers in which poly(p-dioxanone) (PDO) side chains are grafted onto a polysaccharide backbone rather than a continuous linear block as required in the instant linear multiblock copolymer.
Applicant’s arguments filed 09/8/2025 are fully considered and are found not persuasive.
As stated in Final office action filed 04/08/2025, pages 5-8, Prasad teaches biodegradable polymer microsphere, hCG and controlled release, and well as the reduction of the burst release rate of hCG content from 90% to 43% (example 4, and page 19, line 20, Prasad). Regarding the amended limitation of the 1/7 release of hCG content from microsphere, it would reasonably overlap. This 1/7 release of hCG is a result effective variable where a person having ordinary skill in the art would be motivated to experiment using this guidance to achieve this 1/7 release of hCG by adjusting variables to achieve desired result. Therefore, Prasad in view of Kacker, Zhou, and further in view of Lu disclose the controlled-release formulation comprising hCG is stable, effective and advantageous over the hCG formulation known in the art, containing multiple uses to include therapy for increasing the levels of hCG in maintenance of pregnancy, taking care of the needs of a stable and preserved solutions, formulations, and products comprising of hCG or hCG variants and using these product in the field of gynecology.
In regards to the amended claim 1 to specify that the biodegradable multi-block copolymer is of linear architecture and cited reference Lu teaches graft poly(p-dioxanone)(PDO) as a side chain. This argument is moot as rejection by new reference (Steendam), see above.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Steendam is relied upon for the teachings of [poly(c-caprolactone)-co-polyethylene glycol-co-poly(ccaprolactone)]-b-[poly(p-dioxanone)] multi-block copolymer, pre-polymer (A) comprises polyethylene glycol as the water-soluble polymer as specified in the amended claim 1; Kacker is being relied upon for the teachings of poly(ε-caprolactone) (PCL), poly-ethylene-glycol (PEG), poly(L-lactide) and/or a combination thereof, in view of Zhou as drug carriers in microsphere formulation.
In response to applicant's arguments against the references 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).
Therefore, the new prior art of record discloses expected results of the controlled-release formulation comprising hCG is stable, effective and advantageous over the hCG formulation known in the art and thus, a prima facie case has been properly established.
Conclusion
No claims are allowed.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615