DETAILED ACTION
Status of the Claims
Claims 1-10, 12-14, 16 and 17 are pending in the instant application. Claim 15 is withdrawn, as discussed below. Claims 1-10, 12-14, 16 and 17 are being examined on the merits in the instant application.
Newly submitted claim 15 is directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: The claim has been amended from a composition claim reciting an intended use to a method of use claim.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claim 15 withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
Advisory Notice
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All rejections and/or objections not explicitly maintained in the instant office action have been withdrawn per Applicants’ claim amendments and/or persuasive arguments.
Priority
The instant Application claims priority to U.S. Provisional Application No. 63/511,923 (hereafter ‘923) is a continuation-in-part of PCT/US 2022/070910 which claims priority to U.S. Provisional Application No. 63/156,020.
The U.S. effective filing date for claims 1-9 and 11-16 has been determined to be 09/01/2023, the filing date of the instant application. The U.S. effective filing date for claims 10 and 17 has been determined to be 07/05/2023 the filing date of ‘923. The examiner finds no support for the limitation “wherein each polymer microsphere comprises a drug load of the ibrutinib or the zanubrutinib of greater than 30% by weight of the polymer microsphere” (claim 1, lines 6-7) in ‘923. Rather ‘923 discloses a drug loading of greater than 40 wt/wt% (p. 11, [0042]; claims 1, 10 & 16).
Claim Objections
Claim 1 is objected to as fail to comply with 37 CFR 1.121(c)(2) for failing to reproduce the previously presented text of claim 1, particularly the text: “50)”. Applicant should take care to reproduce the text as previously presented even for text of deleted subject matter (MPEP §714(II)(C)).
Claim Rejections - 35 USC § 112(a)
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 1-10 and 12-14 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. This is a New Matter Rejection.
Scope of the Claimed Invention:
Applicant claims a microsphere formulation, comprising: polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor selected from the group consisting of ibrutinib and zanubrutinib and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the ibrutinib or the zanubrutinib of greater than 30% by weight of the polymer microsphere, and wherein the polymer microspheres have a median particle size of between about 20 m and about 60 m and wherein the microsphere formulation is characterized in that not more than about 20% of the ibrutinib or the zanubrutinib has been released within 24 hours of injection into the subject (instant claim 1).
Disclosure of the Instant Application:
The instant Specification discloses that: “[0047] In one aspect, the polymer microspheres may have a particle size of less than 110 µm (D50), including between about 20 µm (D50) and about 60 µm (D50), between about 30 um (D50) and about 50 µm (D₅₀), between about 30 µm (D50) and about 40 µm (D₅₀), between about 35 µm (D₅₀) and about 60 µm (D₅₀), between about 45 µm (D50) and about 60 µm (D₅₀), about 20 µm (D₅₀), about 25 µm (D₅₀), about 30 µm (D50), about 35 µm (D₅₀), about 40 µm (D₅₀), about 45 µm (D₅₀), about 50 µm (D₅₀), about 55 µm (D₅₀), about 60 µm (D₅₀), less than about 60 µm (D₅₀), and any value or range between any two of those particle sizes.
[0048] In some particular aspects, it is contemplated that particle sizes may be as large as 150- 200 µm.” (p. 12, §Particle Size).
Discussion:
Applicant has amended claim 1 to recite, in part, “wherein the polymer microspheres have a median particle size of between about 20 m and about 60 m” which is considered new matter because the examiner finds no disclosure of a particles size of “about 20 m” or “about 60 m” in the as filed Application, 20 m being 20 meters, and 60 m being 60 meters. Therefore, the claims are properly rejected as failing to comply with the written description requirement, for the introduction of new matter, and as the claims contain 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
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-10, 12-14, 16 and 17 remain rejected under 35 U.S.C. 103 as being unpatentable over Benny et al. (“Local Delivery of Poly Lactic-co-glycolic Acid Microspheres Containing Imatinib Mesylate Inhibits Intracranial Xenograft Glioma Growth,” 2009; Clinical Cancer Research Vol. 15, No. 4, pp. 1222-1231) in view of Wang et al. (“Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma,” 2017; Journal of Experimental & Clinical Cancer Research, Vol. 36, No. 1, article 96, pp. 1-13); Yoo et al. (“Phenomenology of the Initial Burst Release of Drugs from PLGA Microparticles,” 2020, ACS Biomaterials Science & Engineering, Vol. 6, pp. 6053-6062) and RICHEY (US 2016/0317453; published November 2016).
Applicants Claims
Applicant claims a microsphere formulation, comprising: polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor selected from the group consisting of ibrutinib and zanubrutinib and (ii) a biodegradable polymer, wherein each polymer microsphere comprises a drug load of the ibrutinib or the zanubrutinib of greater than 30% by weight of the polymer microsphere, and wherein the polymer microspheres have a median particle size of between about 20 m and about 60 m and wherein the microsphere formulation is characterized in that not more than about 20% of the ibrutinib or the zanubrutinib has been released within 24 hours of injection into the subject (instant claim 1).
Claim interpretation: For claims 1-10 and 12-14, claim 1 has been amended to recite “wherein the polymer microspheres have a median particle size of between about 20 m and about 60 m” (claim 1, lines 8-9), which appears to be a clerical error as claims 16 and 17 have been amended to recite median particle size in microns (μm), therefore for treatment in the instant grounds of rejection. The examiner is interpreting claim 1 as reciting wherein the polymer microspheres have a median particle size of between about 20 μm and about 60 μm” (claim 1, lines 8-9), for compact prosecution.
Determination of the scope
and content of the prior art (MPEP 2141.01)
Benny et al. teaches that: “Local Delivery of Poly Lactic-co-glycolic Acid Microspheres Containing Imatinib Mesylate Inhibits Intracranial Xenograft Glioma Growth” (title, see whole document). Benny et al. teaches that: “Glioblastoma multiforme is the most common subtype of primary brain tumor. The long-term survival of these patients remains poor despite a multitude of treatments including surgical resection, followed by radiotherapy and chemotherapy.” (p. 1222, col. 1, lines 1-4). And that: “Imatinib mesylate is now the standard of care for patients with chronic myelogneous leukemia in which the abl pathway is activated. However, the large amounts of imatinib mesylate that are needed to reach therapeutic concentrations in the brain support the need for a local delivery of imatinib mesylate to the tumor site. Moreover, local continuous treatment can eliminate the need of daily administrations and prolong treatment efficiency.” (p. 1222, col. 2, 1st paragraph). And further that: “We have previously reported the development of poly(lactic-co-glycolic) acid (PLGA) microspheres as a local delivery system for endogenous inhibitors of angiogenesis in glioblastoma multiforme. PLGA is a Food and Drug Administration–approved polymer with biodegradability properties that can be designed to control the release kinetics of a drug by varying the polymer composition. In the present study the optimal protocol for imatinib mesylate–loaded microspheres was established.” (p. 1222, col. 2, 2nd paragraph).
Benny et al. teaches that: “Microspheres loaded with imatinib mesylate (provided by Novartis, SW) were prepared using the double emulsion solvent extraction method with slight modifications. Imatinib mesylate was loaded in three different formulated particles made of 200 mg PLGA50:50 (RG502; Boehringer Ingelheim), PLGA75:25, or PLGA85:15 lactic to glycolic acids ratio (20,000 kDa; Birmingham polymers Inc.). Briefly, polymers were dissolved in 0.5 mL of dichloromethane.” (paragraph bridging pp. 1222-1223)(instant claims 4 and 6, ester -terminated PLGA polymers). Benny et al. further teaches that: “Microspheres prepared from all PLGA copolymer ratios exhibited a spherical, intact surface area (Fig. 1A and B). The microspheres had a mean size1 of 33.83 μm in diameter as obtained by a Coulter counter and a ζ potential ranging between -14 to -20 mV (Fig. 1C). The release profile of imatinib mesylate was characterized by a continuous release for 17 to 35 days depending on polymer composition (Fig. 1D).” (p. 1225, §Results, lines 1-8). Benny et al. further teaches that: “The release rate of imatinib mesylate from PLGA85:15 microspheres was significantly slower than from PLGA50:50 and PLGA75:25 microspheres. The loading efficiency of imatinib mesylate in PLGA75:25 was 15.3 ± 0.2 with a release period of 17 days, which was significantly lower than in PLGA50:50 (54.6 ± 0.5 for 17 days) and PLGA85:15 microspheres (57.1 ± 0.8 for 30 days).” (p. 1225, col. 2, lines 9-15)(instant claims 1, “a biodegradable polymer, wherein each polymer comprises a drug load of […] greater than 30%”; claims 2-3, 7, 9, 10-11, 16 and 17; instant claims 12-13, drug release amount per period). Benny et al. teaches injection into mice: “The in vivo effect of imatinib mesylate released from PLGA microspheres was studied in two glioma models: human U87-MG glioblastoma cells in Swiss nude mice, and GL261 murine glioblastoma cells in C57/BL mice. Mice (4- to 6-wk old; Harlan Lab) were inoculated s.c with 1 x 106 GL261 cells or 5 x 106 U87-MG. When the tumors reached the size of 60 mm3 (GL261) or 200 mm3 (U87-MG), the animals were randomly divided into two groups of eight animals each. The first group received a single s.c injection of a 1:1 mixture of 10 mg PLGA50:50 and PLGA85:15 microspheres containing a total of 1.25 mg imatinib mesylate/mice.” (p. 1224, col. 1, 2nd paragraph)(instant claims 14-14).
Ascertainment of the difference between
the prior art and the claims (MPEP 2141.02)
The difference between the rejected claims and the teachings of Benny et al. is that Benny et al. does not expressly teach: (1) the drug species ibrutinib or zanubrutinib; (2) low initial burst release “but not more than 20% […] released within 24 hours” (instant claims 1, 16 & 17); (3) the biodegradable polymer is acid-terminated (claims 8 & 17).
Wang et al. teaches “Ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma” (title, see whole document). Wang et al. teaches that: “Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor, is a novel anticancer drug used for treating several types of cancers. In this study, we aimed to determine the role of ibrutinib on GBM.” (abstract – Background). And concludes that: “Our results indicate that ibrutinib exerts a profound antitumor effect and induces autophagy through Akt/mTOR signaling pathway in GBM cells. Autophagy inhibition promotes the antitumor activity of ibrutinib in GBM. Our findings provide important insights into the action of an anticancer agent combining with autophagy inhibitor for malignant glioma.” (abstract, Conclusions). It would have been prima facie obvious to combine or substitute the imatinib mesylate with ibrutinib in the PLGA microspheres of Benny et al. per the teachings of Wang et al. for treating GBM by local delivery of the PLGA microspheres.
Yoo et al. teaches “Phenomenology of the Initial Burst Release of Drugs from PLGA Microparticles” (title, see whole document), and particularly that: “Poly(lactic-co-glycolic acid) (PLGA) is the most prevalent polymer drug delivery vehicle in use today. There are about 20 commercialized drug products in which PLGA is used as an excipient. In more than half of these formulations, PLGA is used in the form of microparticles (with sizes in the range between 60 nm and 100 μm). The primary role of PLGA is to control the kinetics of drug release toward achieving sustained release of the drug. Unfortunately, most drug-loaded PLGA microparticles exhibit a common drawback: an initial uncontrolled burst of the drug. After 30 years of utilization of PLGA in controlled drug delivery systems, this initial burst drug release still remains an unresolved challenge.” (abstract).
RICHEY teaches “A sustained release microsphere formulation with a high
drug load may be formed by a continuous oil-in-water emulsion process by combining an organic dispersed phase with an aqueous continuous phase.” (abstract, see whole document). And particularly “microsphere formulation with an improved or increased drug load and a low initial burst release” [emphasis added]([0002]). And further that: “It would be desirable to produce a commercially acceptable injectable sustained release microsphere formulation that has both a high drug load and a low initial burst release.” ([0006]).
RICHEY teaches that: “In one embodiment, the buprenorphine drug load of the formulation is about 15% by weight of the microspheres to about 50% by weight of the microspheres and the cosolvent may be present in an amount of up to 50% by weight of the dispersed phase and is capable of increasing the solubility of the buprenorphine relative to the dispersed phase to about 0.1 g/g to about 0.3 g/g.” ([0011]). And further that: “In this embodiment, the amount of buprenorphine is substantially released from the microsphere formulation in about one month, but less than two months, after it is injected into the patient and the formulation has a drug load of about 35% to about 55% and a mean particle size of about 25 μm to about 45 μm.” ([0012]). RICHEY discloses in Table 2 an example particle having a median particle size (50% CVF) of 33.4 microns (Batch 1) and 45.9 microns (Batch 2)(instant claims 1, 16 and 17 – median particle size). The examiner further notes that the instant Specification defines the particle size as Dv50 (p. 18, Table 1) which is being interpreted as equivalent to the CVF (cumulative volume fraction) disclosed by RICHEY in, for example, Table 2.
RICHEY teaches that: “In another embodiment, a sustained release microsphere formulation for injection into a patient includes a dispersed phase comprising a poly (D,L-lactide-co-glycolide) polymer with a ratio of lactic acid to glycolic acid of between about 50:50 to about 100:0, at least one solvent, and a pharmaceutically effective amount of buprenorphine and a continuous phase comprising an aqueous solution; wherein the dispersed phase may be mixed with the continuous phase to form the microsphere formulation. In this embodiment, the amount of buprenorphine is substantially released from the micro sphere formulation over three months, but less than nine months, after it is injected into the patient and the formulation has a drug load of about 30% to about 50% and a mean particle size of about 20 μm to about 45 μm.” ([0014]). The examiner notes that “mean particle size” and “D50 particle size” - or median as defined by Applicant - are considered equivalent or substantially equivalent in the art to which the invention pertains.
RICHEY teaches that: “In one embodiment, the formulation may also have a low or steady state initial burst release.” ([0024]). And that: “In another embodiment, the formulation has an initial in-vivo burst release of not more than three times the highest concentration observed during the sustained portion of the buprenorphine release and in another embodiment, not higher than two times the highest concentration observed during the sustained portion of the buprenorphine release.” ([0008]). And further that: “As shown in FIG. 4, the polymer molecular weight influenced the initial burst rate and release duration. The initial burst of the batch prepared with the lower molecular weight PLGA was higher, batch 1, about 21 ng/ml as compared to 11 ng/ml for batch 2, and the duration of buprenorphine release increased from about 30 days to about 50 days when the higher molecular weight polymer was utilized.” ([0061]).
RICHEY “The PLGA polymers can either be non-end capped having a free
carboxylic acid terminal group, or end-capped, by esterification.” ([0062])(instant claims 8 & 16, acid-terminated). The examiner further cites RESOMER® Product range (Evonik Industries – 2015) as clearly teaching “End group Control various polymer properties (degradation and water uptake) by modifying end-groups: Acid (A) or Ester (E)” (p. 3, §RESOMER® Select naming, box “E”).
Finding of prima facie obviousness
Rationale and Motivation (MPEP 2142-2143)
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 produce a Local Delivery of Poly Lactic-co-glycolic Acid Microspheres for treatment of cancer such as Glioblastoma multiforme (GBM), as suggested by Benny et al., the anticancer microspheres containing a Bruton’s tyrosine kinase inhibitor such as ibrutinib, as suggested by Wang et al. as suitable for treating GBM, and further to minimize the burst release of the drug (release within 24 hours) as this continues to be a problem with PLGA microspheres per the teaching of Yoo et al., the low burst release microspheres being also taught by RICHEY.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention it would have required no more than an ordinary level of skill in the art to produce microspheres such as those disclosed by Benny et al. and RICHEY et al. per the teaching therein and in view of the ordinary level of skill in the art to which the invention pertains. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103(a).
Response to Arguments:
Applicant's arguments filed 02/09/2026 have been fully considered but they are not persuasive.
Applicant argues that: “ibrutinib and zanubrutinib have a significantly different structure from Imatinib mesylate and, consequently, a significantly different target specificity and binding mechanism.” And that: “The structures of Imatinib mesylate, ibrutinib, and zanubrutinib are shown below. The structural similarities of ibrutinib and zanubrutinib are apparent: […].” And that: “Imatinib is a 2-phenylaminopyrimidine derivative designed to fit into the ATP-binding pocket of the BCR-ABL tyrosine kinase. It is a reversible inhibitor (non-covalent). It does not form a covalent bond with a cysteine residue like the BTK inhibitors.” And that: “Ibrutinib and zanubrutinib, on the other hand, each feature an acrylamide group that acts as a "warhead" to form an irreversible covalent bond with the Cys48 l residue in the BTK binding pocket.” And further that: “Applicant submits that, other than being TKls, there is nothing about imatinib on the one hand, and ibrutinib and zanubrutinib on the other, that would instruct one about the other in terms of behavior in a microsphere.” (p. 3).
The examiner does agrees the different compounds have different structures, however the prior art clearly teaches Imatinib Mesylate for the treatment of Glioblastoma multiforme (GMB) and the advantage of microspheres containing the same relative to conventional treatments. Particularly Benny et al. teaches microspheres loaded with imatinib mesylate - “We have previously reported the development of poly(lactic-co-glycolic) acid (PLGA) microspheres as a local delivery system for endogenous inhibitors of angiogenesis in glioblastoma multiforme. PLGA is a Food and Drug Administration–approved polymer with biodegradability properties that can be designed to control the release kinetics of a drug by varying the polymer composition. In the present study the optimal protocol for imatinib mesylate–loaded microspheres was established.” (p. 1222, col. 2, 2nd paragraph). Wang et al. teaches ibrutinib, a Bruton’s tyrosine kinase inhibitor, exhibits antitumoral activity and induces autophagy in glioblastoma. Thus, it would have been prima facie obvious to combine or substitute the imatinib mesylate with ibrutinib in the PLGA microspheres of Benny et al. per the teachings of Wang et al. for treating GBM by local delivery of the PLGA microspheres. Additionally, while some degree of predictability is required for an obviousness rejection absolute predictability is not required (MPEP §2143.02-II). Given that the microspheres of the instantly claimed invention are made by a method according to USPN 5,945,126 (instant Specification p. 15, last line), as are the microspheres of RICHEY ([0030]), one of ordinary skill would clearly have had a reasonable expectation of making drug containing microspheres using the methods described by RICHEY, the drug being imatinib mesylate with ibrutinib, or ibrutinib alone.
Applicant further argues that: “Further as to the issue of low initial burst release ("but not more than 20% [ ... ] released within 24 hours"), which is now an element in all of the independent claims, Applicant submits that Yoo continues to be important to this analysis. Yoo is the latest in time (2020) of all of the cited references and states clearly that as of 2020, "PLGA is not an exception in terms of the initial burst of the drug; overcoming this problem remains a technological problem for PLGA-based drug delivery systems, too" (Yoo, p. 6053) (emphasis added). Indeed, Yoo states, "After 30 years of utilization of PLGA in controlled drug delivery systems, this initial burst drug release remains an unresolved challenge" (Yoo, Abstract). The teachings of Richey have been published since at least 2014 (the cited reference is the publication of a continuing application) and did not, according to Yoo, resolve the burst issue (and, further to the type of drug issue, Richey's teachings are directed to buprenorphine, which is even more structurally dissimilar from the BTK inhibitors than imatinib mesylate ).” (p. 4, 1st paragraph).
In response the examiner argues that Given that the microspheres of the instantly claimed invention are made by a method according to USPN 5,945,126 (instant Specification p. 15, last line), as are the microspheres of RICHEY ([0030]), one of ordinary skill would clearly have had a reasonable expectation of making drug containing microspheres using the methods described by RICHEY, the drug being imatinib mesylate with ibrutinib, or ibrutinib alone. One of ordinary skill would have understood the factors affecting burst release (i.e. drug release in the 1st 24-hours) and have been able to reduce the same to a desired level. Particularly, RICHEY teaches that: “In one embodiment, the formulation may also have a low or steady state initial burst release.” ([0024]). And that: “In another embodiment, the formulation has an initial in-vivo burst release of not more than three times the highest concentration observed during the sustained portion of the buprenorphine release and in another embodiment, not higher than two times the highest concentration observed during the sustained portion of the buprenorphine release.” ([0008]). And further that: “As shown in FIG. 4, the polymer molecular weight influenced the initial burst rate and release duration. The initial burst of the batch prepared with the lower molecular weight PLGA was higher, batch 1, about 21 ng/ml as compared to 11 ng/ml for batch 2, and the duration of buprenorphine release increased from about 30 days to about 50 days when the higher molecular weight polymer was utilized.” ([0061]).
Applicant further states that: “Applicant's invention as disclosed and claimed in this application, for ibrutinib and zanubrutinib -encapsulated microspheres only, resolves the burst release issue. Surprisingly, this application does so using high drug loading (capable of subcutaneous or intramuscular injection) where Benny used "local injection of microspheres loaded with a low concentration of imatinib" (Benny, p. 1222) (emphasis added; Applicant notes that Benny reveals loading efficiency but not drug load (Benny, p. 1225), at least as far as Applicant could decipher, and merely refers to it as "low" for local injection), for similar sized microspheres. This is surprising and inventive. It is well known that the "[a]mount of drug loading in the drug delivery matrix plays a significant role on the rate and duration of drug release. Matrices having higher drug content possess a larger initial burst release than those having lower content because of their smaller polymer to drug ratio" (Makadia, p. 10) (emphasis added); "Higher drug loading means that a greater proportion of drugs will be encapsulated in the microspheres, and their effect on the polymer will be more prominent" (Hua, p. 1347). In Applicant's case, however, a high drug load of a TKI had a lower initial burst than a low drug load of a TKI (Benny), for similar sized microspheres. For all of these reasons, Applicant respectfully requests that the Office withdraw the rejection of claims 1-10 and 12-17 in under rejected under 35 U.S.C. 103 as being unpatentable over Benny in view of Wang, Yoo, and Richey.” (paragraph bridging pp. 4-5).
In response the examiner the claims are open-ended and do not require both ibrutinib and zanubrutinib, and the biodegradable polymer is not limited in the base claim. Therefore Applicants point regarding what is claim is not clear, as MPEP §2111.03 makes clear that: “The transitional term "comprising", which is synonymous with "including," "containing," or "characterized by," is inclusive or open-ended and does not exclude additional, unrecited elements or method steps.” MPEP §2117 makes clear that “A "Markush" claim recites a list of alternatively useable members.” Claim 1 reciting “A microsphere composition comprising: polymer microspheres, each polymer microsphere comprising: (i) a BTK inhibitor selected from the group consisting of ibrutinib and zanubrutinib, and (ii) a biodegradable polymer […].” Which is open-ended, and only requires “a BTK inhibitor selected from the group consisting of ibrutinib and zanubrutinib” The disclosed invention informs one as to what is claimed by it is improper import limitations into the claims (Broadest Reasonable Interpretation - MPEP §2111). Additionally, as discussed above the microspheres of the instantly claimed invention are made by a method according to USPN 5,945,126 (instant Specification p. 15, last line), as are the microspheres of RICHEY ([0030]), one of ordinary skill would clearly have had a reasonable expectation of making drug containing microspheres using the methods described by RICHEY, the drug being imatinib mesylate with ibrutinib, or ibrutinib alone. RICHEY teaches “A sustained release microsphere formulation with a high drug load may be formed by a continuous oil-in-water emulsion process by combining an organic dispersed phase with an aqueous continuous phase.” (abstract, see whole document). RICHEY further teaches that: “microsphere formulation with an improved or increased drug load and a low initial burst release” [emphasis added]([0002]). And further that: “It would be desirable to produce a commercially acceptable injectable sustained release microsphere formulation that has both a high drug load and a low initial burst release.” ([0006]). Therefore, a high drug loading and low initial burst release in drug containing microspheres does not appear to be surprising as this is clearly taught by RICHEY.
Additional prior art not relied on for rejection:
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The examiner cites USPN 5,945,126 as cited by both the instant Application (Specification p. 15, last line) and RICHEY ([0030]).
Conclusion
Claims 1-10, 12-14, 16 and 17 are pending and have been examined on the merits. Claims 1-10 and 12-14 are rejected under 35 U.S.C. 112(a)(new matter) and claims 1-10, 12-14, 16 and 17 are rejected under 35 U.S.C. 103. No claims allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IVAN A GREENE whose telephone number is (571)270-5868. The examiner can normally be reached M-F, 8-5 PM PST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached on (571) 272-0827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IVAN A GREENE/Examiner, Art Unit 1619
/TIGABU KASSA/Primary Examiner, Art Unit 1619
1 The examiner notes that “mean particle size” and “D50 particle size” - or median as defined by Applicant - are considered equivalent or substantially equivalent in the art to which the invention pertains.
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