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 .
DETAILED ACTION
Claims 67-92 are pending and under examination on their merits.
Claim Objections
Claim 76 is objected to because of the following informalities: “wherein the combined preparation rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently.” The word “of” is missing between “combined preparation” and “rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase.” Furthermore, the verb tense is incorrect because “the combined preparation” is singular.
Appropriate correction is required.
Response to Arguments
Applicant's arguments filed 2/6/2026 have been fully considered but they are not persuasive.
Applicant argues against the rejection of claims under 35 U.S.C. 103 as obvious over Baert in view of Bookbinder as evidenced by Locke on the grounds that Bookbinder and Locke teach that when hyaluronidase is administered in combination with another drug, the result would be a rapid systemic distribution and increased dispersion and absorption, not a prolonged, extended, sustained release. Applicant argues that a rapid systemic distribution and increase dispersion and absorption is the opposite of a prolonged, extended, sustained release (Arguments, bottom paragraph on page 10). Applicant alleges unexpected results, referring to the Examples 2-4 of the specification (Examples 2-4, Arguments, middle paragraph on page 11).
In response, these arguments are unpersuasive and Applicant’s results are neither unexpected nor nonobvious. Baert already teaches that the subcutaneous route of administering rilpivirine nanoparticles resulted in the most stable plasma levels and exhibited sustained release of rilpivirine from the nanoparticles (Abstract). The person of ordinary skill in the art would have expected that adding hyaluronidase would have increased the rate of delivery through the skin barrier but would not have expected hyaluronidase to alter the fundamental kinetics of the release of rilpivirine from the nanoparticles, which drive the long-lasting pharmacokinetic profile. The nanoparticles consist entirely of the drug coated with a surface modified to impart physical stability (Baert, page 504, right column, 3.1. Preliminary characterization of the nanosuspensions, paragraph 1; Baert page 505, left column, 3.1.2. Impact of surfactant; Elan’s NanoCrystals, first paragraph after figure on page 1). Bookbinder teaches that hyaluronidase opens channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30). Bookbinder teaches that subcutaneous administration of molecules in the presence of a hyaluronidase facilitates their rapid systemic distribution (column 8, lines 30-33). Thus, the person of ordinary skill in the art would have expected that the hyaluronidase facilitates diffusion through the skin barrier and enhances the delivery of Baert’s nanoparticles through the skin and increases systemic distribution, which includes distribution into the bloodstream. These teachings are not mutually exclusive with the prolonged release of rilpivirine from nanoparticles taught by Baert. The person of ordinary skill in the art would have had a reasonable expectation of success in combining hyaluronidase, which facilitates diffusion of therapeutic molecules and proteins through the skin barrier, with the sustained release of rilpivirine nanoparticles taught by Baert.
Regarding the nonstatutory double patenting rejections of record, Applicant requests that the Examiner hold these double patenting rejections in abeyance until an allowable claim is identified (Arguments, page 15, Applicant’s Response).
Per MPEP 804, part (I)(B)(1), only compliance with objections or requirements as to form not necessary for further consideration of the claims may be held in abeyance until allowable subject matter is indicated.
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.
(New Rejection Necessitated by Amendment) Claims 67-92 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 67, 76, and 83 recite “wherein a prolonged, extended, sustained release of rilpivirine or a pharmaceutically acceptable salt thereof into the blood plasma is maintained.” There are at least two different reasonable interpretations of this limitation, rendering the claims indefinite. In one interpretation, the prolonged, extended, sustained release of rilpivirine is maintained during the time interval of about three months to about two years. In a second interpretation, the prolonged, extended, sustained release of rilpivirine is maintained in combination with the hyaluronidase. Under the first interpretation, the limitation requires the release for the given time period. Under the second interpretation, the release is relative to rilpivirine administered without the hyaluronidase.
Claims 68-75, 77-82, and 84-92 are rejected for depending from a rejected base claim and not rectifying the source of indefiniteness discussed above.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
(New Rejection Necessitated by the Amendment) Claims 90-92 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 90-92 each limit the recombinant human hyaluronidase to PH20. However, claims 90-92 each depend from claims that require the hyaluronidase is a recombinant human hyaluronidase comprising the amino acid sequence of SEQ ID NO: 1. SEQ ID NO: 1 is PH20, so claims 90-92 do not further limit the subject matter of the claims upon which they depend.
Applicant may cancel the claims, amend the claims to place the claims in proper dependent form, rewrite the claims in independent form, or present a sufficient showing that the dependent claims comply with the statutory requirements.
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 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.
The following rejections are necessitated by the amendment.
Claims 67-71, 73-78, 80-85, and 87-92 are rejected under 35 U.S.C. 103 as being unpatentable over Baert et al. (European Journal of Pharmaceutics and Biopharmaceutics 72.3 (2009): 502-508) in view of Bookbinder (US 7,767,429 B2) and as evidenced by Locke et al. (Drug delivery 26.1 (2019): 98-106).
Claim 67 is interpreted as requiring that the release of rilpivirine from the nanoparticles is non-zero during the duration of the time interval.
Baert teaches a method of administering rilpivirine (TMC278 nanosuspensions) in the form of micro- or nanoparticles in suspension by intramuscular or subcutaneous injection to beagle dogs (Abstract, Figure 3, Table 2). Baert teaches that rilpivirine is a candidate for long-acting therapeutic and prophylactic treatment for HIV (page 502, right column, bottom paragraph). Baert teaches that the nanoparticles maintain rilpivirine plasma concentrations above 5 ng/mL for at least three months (Fig. 3), thus Baert teaches “prolonged, extended, and sustained release of rilpivirine in blood plasma.” Baert teaches the mean plasma concentration profiles of rilpivirine nanosuspensions in beagle dogs after subcutaneous dosing of 400 and 800 nm nanosuspensions at 5 or 20 mg/kg (Fig. 3). Baert teaches that plasma concentrations exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4).
In addition, Baert teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains and its potent antiviral effect has been confirmed in a dose-finding study in treatment-naïve HIV patients (paragraph bridging pages 502-503). Therefore, Baert teaches a subject tin need thereof, i.e. the HIV patients.
Baert does not teach that rilpivirine is administered in combination with a hyaluronidase that is administered by intramuscular or subcutaneous injection.
Baert does not teach that the hyaluronidase is administered with rilpivirine intermittently at a time interval of about three months to about two years.
Bookbinder teaches that subcutaneous administration of molecules in the presence of a hyaluronidase facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that hyaluronidase opens channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the rilpivirine nanoparticle suspension of Baert with the hyaluronidase enzyme of Bookbinder and to administer the combination to a subject in order to treat HIV infection. The person of ordinary skill in the art would have been motivated to enhance systemic distribution of the rilpivirine in treating HIV infection. One of ordinary skill would have had a reasonable expectation of success given the teaching of Bookbinder that hyaluronidase facilitates the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they are less than 500 nm in size. Because the nanoparticles of Baert are on the order of 200 nm or 400 nm (Abstract), which is less than the 500 nm size limit taught by Bookbinder, the person of ordinary skill in the art would have had a reasonable expectation of success in enhanced diffusion of rilpivirine nanoparticles.
It would have been further obvious to routinely optimize the dosage regimen of the formulation of Baert modified by Bookbinder. The person of ordinary skill in the art would have had a reasonable expectation of success given that rilpivirine has therapeutic efficacy for the treatment of HIV infection as taught by Baert (paragraph bridging pages 502-503).
Regarding the time interval for administration in claim 67 (“wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years”) and claim 69 (“wherein the time interval is about three months to about six months”), Baert teaches that plasma concentrations exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4). The plasma concentration in subjects administered 20 mg/kg of rilpivirine in 400 nm nanoparticle suspensions is about 15 ng/mL after 42 days (Figure 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the timing of the delivery of the combination of rilpivirine nanoparticle suspensions and hyaluronidase in order to optimize the pharmacokinetic profile of rilpivirine in vivo. The person of ordinary skill in the art would have had a reasonable expectation of success given that the plasma concentration was already near the theoretical optimum of 20 ng/ml after 42 days. Furthermore, administration of hyaluronidase in combination with the rilpivirine nanoparticle suspensions would have been expected to increase the bioavailability of rilpivirine, thus increasing the area under the curve (AUC), as evidenced by Locke (page 98, right column, lines 1-3).
Regarding claim 76, Baert does not teach that rilpivirine in the form of nanoparticles in suspension in a combined preparation with hyaluronidase.
However, as discussed above with respect to claim 67 and its dependents, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine and hyaluronidase for the treatment of HIV, thus a combined preparation of rilpivirine and hyaluronidase would also have been obvious.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 76) and “wherein the time interval is about three months to about six months (claim 78), these limitations pertain to an intended use of the preparation and do not further limit the structure of the claimed product.
Regarding claim 83, Baert does not teach a kit comprising rilpivirine in the form of nanoparticles in suspension and a hyaluronidase.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate Baert’s rilpivirine nanoparticle suspension together with Bookbinder’s hyaluronidase in a kit for commercial use. The person of ordinary skill in the art would have been motivated to facilitate performing a method of treatment of HIV infection by medical professionals or patients. The person of ordinary skill in the art would have had a reasonable expectation of success in this endeavor.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 83) and “wherein the time interval is about three months to about six months” (claim 85), these limitations pertain to an intended use of the kit and do not further limit the structure of the claimed kit.
Regarding claim 68, 77, 84, and 90-92, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of SEQ ID NO: 1.” Bookbinder’s SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1 from residues 36 to 478 (OA Appendix A). Thus, Bookbinder teaches C- and N-terminal truncations of PH20 that include the instant SEQ ID NO: 1. Bookbinder also teaches that the 36-478 fragment of recombinant human hyaluronidase (rHuPH20) is both soluble and active (Bookbinder claim 7). Bookbinder teaches that C-terminal truncations of PH20 are secreted proteins (lines 18-20 of column 26). Bookbinder’s SEQ ID NO: 1 is recombinant human hyaluronidase PH20 (lines 59-62 of column 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use any one of the N- and C-terminal truncations of PH20 taught by Bookbinder in the method of Baert and Bookbinder. The person of ordinary skill in the art would have been motivated by Bookbinder’s teaching that these fragments, including amino acid residues 36-478 of SEQ ID NO: 1, retain catalytic activity while having improved solubility (Bookbinder claim 7 and liens 18-20 of column 26).
Regarding claims 70-71, it would have been obvious to the person of ordinary skill in the art to routinely optimize the injection protocol of Baert’s rilpivirine nanoparticle suspension with Bookbinder’s hyaluronidase in order to optimize the pharmacokinetic profile of rilpivirine in vivo. The person of ordinary skill in the art would have envisaged a finite number of options for delivery of the compounds (simultaneously and sequentially) and the person of ordinary skill in the art would have had a reasonable expectation of success in either option. In the case of sequential injection, the person of ordinary skill in the art would have been motivated to first inject the hyaluronidase in order to open channels in the interstitial space through degradation of glycosaminoglycans (Bookbinder column 8, lines 2-5) and subsequently inject Baert’s rilpivirine nanoparticle suspension such that the nanoparticles would have diffused through the open channels.
Regarding claim 73, 80, and 87, the specification defines "average effective particle size" as the volume-based median particle diameter: the diameter below which 50% by volume of the particle population is found (specification page 12, lines 1-3).
Baert teaches that the particle size of the nanoparticles is less than 1 micron (200 nm, 400 nm, and 800 nm; see Abstract), but Baert does not teach the average effective particle size. Baert’s particle size is the mean volume diameter of the particles (page 503, right column, 2.2. Particle size determination and stability testing, paragraph 1).
However, since Baert is capable of producing three discrete particle sizes, all less than 1 micron, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the particle size distribution of the nanoparticles. The person of ordinary skill in the art would have had a reasonable expectation of success given that Baert already tests the production of three different sizes, each of which is less than 1 micron.
Regarding claim 74, Baert teaches development of a long-acting injectable formulation with nanoparticles of rilpivirine for HIV treatment. See Title and the paragraph bridging page 502 with page 503. Baert’s disclosure does not limit HIV treatment to any HIV subtype; and thus, would necessarily include treatment of HIV-1 infection. Baert also teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains (Baert, page 503, left column, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine nanoparticle suspension in combination with hyaluronidase in order to treat HIV-1 infection. The person of ordinary skill in the art would have had a reasonable expectation of success given that rilpivirine has known therapeutic efficacy against a broad range of wild-type and HIV-mutant strains (Baert, page 503, left column, paragraph 1).
Regarding claim 75, 82, and 89, Baert prepares nanoparticles from rilpivirine in its form as a free base (page 503, 2.1 Test compounds and formulations, paragraph 1).
Regarding claim 81, treatment of HIV-1 is an intended use of the product and does not further limit the structure of the claimed product. Baert’s disclosure does not limit HIV treatment to any HIV subtype; and thus, would necessarily include treatment of HIV-1 infection.
Regarding claim 88, treatment of HIV-1 does not further limit the structure of the claimed kit.
Claims 72, 79, and 86 are rejected under 35 U.S.C. 103 as being unpatentable over Baert et al. (European Journal of Pharmaceutics and Biopharmaceutics 72.3 (2009): 502-508) in view of Bookbinder (US 7,767,429 B2) and as evidenced by Locke et al. (Drug delivery 26.1 (2019): 98-106), as applied to claims 67-71, 73-78, 80-85, and 87-89 above, further evidenced by Elan’s NanoCrystals (2000, website).
See discussion of Baert and Bookbinder above, which is incorporated into this rejection as well.
Regarding claim 72, 79, and 86, Baert’s nanoparticles are formulated as nanocrystals with poloxamer 338 as a surfactant (Abstract, page 503, left column “2.1. Test compounds and formulations” paragraph 2). The drug (rilpivirine) is thinly coated with the surface modifier poloxamer 338 (i.e. adsorbed) to impart physical stability, as evidenced by Elan’s NanoCrystals™ (page 2, first paragraph after second image).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
The following rejections are necessitated by the amendment.
Claims 67-92 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37-42, 44-48, and 50-54 of copending Application No. 18/037,218 (‘218) in view of Baert et al. (European Journal of Pharmaceutics and Biopharmaceutics 72.3 (2009): 502-508) as evidenced by Elan’s NanoCrystals™.
Claim 67 is interpreted as requiring that the release of rilpivirine from the nanoparticles is non-zero during the duration of the time interval.
Claim 37 of ‘218 recites a method for the treatment or prevention of a disease in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a drug in the form of nanoparticles in suspension by intramuscular injection or subcutaneous injection, wherein the drug is administered in combination with a hyaluronidase that is administered by intramuscular injection or subcutaneous injection and wherein the drug and the hyaluronidase are administered intermittently at a time interval of about three months to about two years.
Claim 38 of ‘218 recites that the hyaluronidase is rHuPH20 comprising SEQ ID NO: 1.
Claim 39 of ‘218 recites that the drug and the hyaluronidase are administered simultaneously or sequentially.
Claim 40 of ‘218 recites that the drug and the hyaluronidase are administered as a combined pharmaceutical pr composition.
Claim 41 of ‘218 recites that the drug and the hyaluronidase are administered in separate pharmaceutical compositions.
Claim 42 of ‘218 recites that the disease is HIV.
Claim 44 of ‘218 is drawn to a product comprising a drug and a hyaluronidase as a combined preparation for simultaneous or sequential use in therapy by intramuscular injection or subcutaneous injection, wherein the drug is in the form of nanoparticles in suspension and wherein the drug and the hyaluronidase are administered intermittently at a time interval of about three months to about two years.
Claim 45 of ‘218 requires that the hyaluronidase is rHuPH20 comprising SEQ ID NO: 1.
Claim 46 of ‘218 recites that the drug and the hyaluronidase are in a combined pharmaceutical composition.
Claim 47 of ‘218 recites that the drug and the hyaluronidase are in separate pharmaceutical compositions.
Claim 48 of ‘218 recites that the drug is for treatment of HIV.
Claim 50 of ‘218 is drawn to a kit comprising a drug and a hyaluronidase, wherein the drug is in the form of micro- or nanoparticles in suspension.
Claim 51 of ‘218 recites that the hyaluronidase is rHuPH20 comprising SEQ ID NO: 1.
Claim 52 of ‘218 recites that the drug and the hyaluronidase are administered as a combined pharmaceutical composition.
Claim 53 of ‘218 recites that the drug and the hyaluronidase are administered in separate pharmaceutical compositions.
Claim 54 of ‘218 recites that the drug is for the treatment of HIV.
Claims 37-42, 44-48, and 50-54 of ‘218 do not recite that the drug is rilpivirine.
Baert teaches a method of administering rilpivirine in the form of micro- or nanoparticles in suspension by intramuscular or subcutaneous injection to beagle dogs (Abstract, Figure 3, Table 2). Baert teaches that rilpivirine is a candidate for long-acting therapeutic and prophylactic treatment for HIV (page 502, right column, bottom paragraph). Baert teaches that the nanoparticles maintain rilpivirine plasma concentrations above 5 ng/mL for at least three months (Fig. 3), thus Baert teaches “prolonged, extended, sustained release of rilpivirine in blood plasma.” Baert teaches the mean plasma concentration profiles of rilpivirine nanosuspensions in beagle dogs after subcutaneous dosing of 400 and 800 nm nanosuspensions at 5 or 20 mg/kg (Fig. 3). Baert teaches that plasma concentrations exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to replace the generic drug in claims 37-42, 44-48, and 50-54 of ‘218 with Baert’s rilpivirine because Baert’s rilpivirine is formulated as nanoparticles in suspension for long-acting therapeutic treatment for HIV. The person of ordinary skill in the art would have had a reasonable expectation of success given that rilpivirine is a drug for the treatment of HIV, which is within the scope of the method of claims 37-42 of ‘218.
Instant claim 68 is obvious over claim 38 in view of Baert.
Instant claim 69 is obvious over claim 37 of ’218 in view of Baert because the time interval of three months to six months overlaps with the time interval of three months to two years.
Instant claims 70-71 are obvious over claims 39-41 of ‘218 in view of Baert.
Instant claim 76 is obvious over claims 44 and 46-47 of ‘218 in view of Baert.
Instant claim 77 is obvious over claim 45 of ‘218 in view of Baert.
Instant claim 78 is obvious over claim 44 of ‘218 in view of Baert because the time interval for administration is an intended use of the product that does not further limit the structure of the claimed product.
Regarding instant claim 81, treatment of HIV-1 is an intended use of the product and does not further limit the structure of the claimed product, so claim 81 is also obvious over claim 44 of ‘218 in view of Baert.
Instant claim 83 is obvious over claim 50 of ‘218 in view of Baert.
Instant claim 84 is obvious over claim 51 of ‘218 in view of Baert.
Instant claim 85 is obvious over claim 50 of ‘218 in view of Baert because the time interval for administration is an intended use of the kit that does not further limit the structure of the claimed kit.
Regarding instant claim 88, treatment of HIV-1 is an intended use of the kit and does not further limit the structure of the claimed kit, so claim 88 is also obvious over claim 50 of ‘218 in view of Baert.
Regarding claim 72, 79, and 86 Baert’s nanoparticles are formulated as nanocrystals with poloxamer 338 as a surfactant (Abstract, page 503, left column “2.1. Test compounds and formulations” paragraph 2). The drug (rilpivirine) is thinly coated with the surface modifier poloxamer 338 (i.e. adsorbed), as evidenced by Elan’s NanoCrystals™ (page 2, first paragraph after second image).
Regarding claim 73, 80, and 87, the specification defines "average effective particle size" as the volume-based median particle diameter: the diameter below which 50% by volume of the particle population is found (specification page 12, lines 1-3).
Baert teaches that the particle size of the nanoparticles is less than 1 micron (200 nm, 400 nm, and 800 nm; see Abstract), but Baert does not teach the average effective particle size. Baert’s particle size is the mean volume diameter of the particles (page 503, right column, 2.2. Particle size determination and stability testing, paragraph 1).
However, since Baert is capable of producing three discrete particle sizes, all less than 1 micron, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the particle size distribution of the nanoparticles. The person of ordinary skill in the art would have had a reasonable expectation of success given that Baert already tests the production three different sizes, each of which is less than 1 micron.
Regarding claim 74, claims 37-42, 44-48, and 50-54 of ‘218 do not recite that the disease is HIV-1, although claim 42 requires that the disease is HIV.
Baert teaches development of a long-acting injectable formulation with nanoparticles of rilpivirine for HIV treatment. See Title and the paragraph bridging page 502 with page 503. Baert’s disclosure does not limit HIV treatment to any HIV subtype; and thus, would necessarily include treatment of HIV-1 infection. Baert also teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine nanoparticle suspension in combination with hyaluronidase in order to treat HIV-1 infection. The person of ordinary skill in the art would have had a reasonable expectation of success given that rilpivirine has known therapeutic efficacy against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
Regarding claim 75, 82, and 89, Baert prepares nanoparticles from rilpivirine in its form as a free base (page 503, 2.1 Test compounds and formulations, paragraph 1).
This is a provisional nonstatutory double patenting rejection.
Claim 67-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 40, 46, and 60 of U.S. Patent No. RES0,189 E (‘189E”) in view of Baert et al. (European Journal of Pharmaceutics and Biopharmaceutics 72.3 (2009): 502-508) and Bookbinder (US 7,767,429 B2), as evidenced by Locke et al. (Drug delivery 26.1 (2019): 98-106) and by Elan’s NanoCrystals (2000, website).
Claim 67 is interpreted as requiring that the release of rilpivirine from the nanoparticles is non-zero during the duration of the time interval.
Claim 1 of ‘189E recites a method of treating HIV infection in a subject comprising administering to the subject an aqueous parenteral formulation comprising an amount of TMC278, wherein the aqueous parenteral formulation is administered intermittently by subcutaneous or intramuscular administration at a time interval that is once every month or once every four weeks and wherein the amount of TMC278 is effective in keeping a minimum blood plasma level of TMC278 in the subject during the time interval, and the minimum blood plasma level is about 5 ng/mL to about 500 ng/mL.
Claim 2 of ‘189E recites the formulation is administered intramuscularly.
Claim 40 of ‘189E recites “wherein the aqueous parenteral formulation further comprises poloxamer 338.”
Claim 46 of ‘189E recites a method of treating HIV infection in a subject comprising administering to the subject an aqueous parenteral formulation comprising TMC278 and a carrier, wherein the aqueous parenteral formulation is administered intermittently by intramuscular administration at a time interval that is once every two months, and wherein the amount of TMC278 is effective in keeping a minimum blood plasma level of TMC278 in the subject during the time interval, and the minimum blood plasma level is about 5 ng/mL to about 500 ng/mL
Claim 60 of ‘189E recites “wherein the aqueous parenteral formulation further comprises poloxamer 338.”
Claims 1-2, 40, 46, and 60 of ‘189E do not recite that TMC278 (synonym for rilpivirine) is in the form of micro- or nanoparticles in suspension or that TMC278 is administered with a hyaluronidase.
Baert teaches a method of administering rilpivirine in the form of micro- or nanoparticles in suspension by intramuscular or subcutaneous injection to beagle dogs (Abstract, Figure 3, Table 2). Baert teaches that rilpivirine is a candidate for long-acting therapeutic and prophylactic treatment for HIV (page 502, right column, bottom paragraph). Baert teaches that the nanoparticles maintain rilpivirine plasma concentrations above 5 ng/mL for at least three months (Fig. 3), thus Baert teaches “prolonged, extended, sustained release of rilpivirine in blood plasma.” Baert teaches the mean plasma concentration profiles of rilpivirine nanosuspensions in beagle dogs after subcutaneous dosing of 400 and 800 nm nanosuspensions at 5 or 20 mg/kg (Fig. 3). Baert teaches that plasma concentrations exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate TMC278 (rilpivirine) as a nanoparticle suspension in the method of 1-2, 40, 46, and 60 of ‘189E such that the TMC278 formulation would have sustained plasma concentrations over a longer time interval. The person of ordinary skill in the art would have been motivated by the teaching of Baert, which suggests that nanoparticles of TMC278 are effective in maintaining plasma concentrations above 5 ng/mL for at least three months (Fig. 3). The person of ordinary skill in the art would have had a reasonable expectation of success in both the nanoparticle TMC278 formulation and the longer time interval between intermittent administrations of the formulation.
Bookbinder teaches that subcutaneous administration of molecules in the presence of a hyaluronidase facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that hyaluronidase opens channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the TMC278 (rilpivirine) nanoparticle suspension of claims 1-2, 40, 46, and 60 of ‘189E modified by Baert with the hyaluronidase enzyme of Bookbinder and to administer the combination to a subject in order to treat HIV infection. The person of ordinary skill in the art would have been motivated to enhance systemic distribution of rilpivirine. One of ordinary skill would have had a reasonable expectation of success given the teaching of Bookbinder that hyaluronidase facilitates the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they are less than 500 nm in size. Because the nanoparticles of Baert are on the order of 200 nm or 400 nm (Abstract), which is less than the 500 nm size limit taught by Bookbinder, the person of ordinary skill in the art would have had a reasonable expectation of success in enhanced diffusion of rilpivirine nanoparticles.
Regarding the time interval for administration in claim 67 (“wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years”) and claim 69 (“wherein the time interval is about three months to about six months”), claims 1-2, 40, 46, and 60 of ‘189E do not recite that the time interval is about three months.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to increase the time interval for the administration of rilpivirine nanoparticle suspensions and hyaluronidase in order to optimize the pharmacokinetic profile of rilpivirine in vivo. The person of ordinary skill in the art would have had a reasonable expectation of success given that Fig. 3 of Baert teaches that the plasma concentration exceeds 5 ng/mL for three months. In addition, administering rilpivirine in combination with a hyaluronidase would have been expected to enhance the delivery of rilpivirine into interstitial spaces, thus increasing the plasma concentration and increasing the area under the curve as evidenced by Locke et al. (page 98, right column, lines 1-3).
Regarding claim 76, claims 1-2, 40, 46, and 60 of ‘189E do not recite and Baert does not teach that rilpivirine in the form of nanoparticles in suspension in a combined preparation with hyaluronidase.
However, as discussed above with respect to claim 67 and its dependents, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine and hyaluronidase for the treatment of HIV, thus a combined preparation of rilpivirine and hyaluronidase would also have been obvious.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 76) and “wherein the time interval is about three months to about six months (claim 78), these limitations pertain to an intended use of the preparation and do not further limit the structure of the claimed product.
Regarding claim 83, claims 1-2, 40, 46, and 60 of ‘189E do not recite and Baert does not teach a kit comprising a rilpivirine in the form of nanoparticles in suspension and a hyaluronidase.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the rilpivirine of claims 1-2, 40, 46, and 60 of ‘189E modified by Baert as a nanoparticle suspension together with Bookbinder’s hyaluronidase in a kit for commercial use. The person of ordinary skill in the art would have been motivated to facilitate performing a method of treatment of HIV infection by medical professionals or patients. The person of ordinary skill in the art would have had a reasonable expectation of success in this endeavor.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 83) and “wherein the time interval is about three months to about six months” (claim 85), these limitations pertain to an intended use of the kit and do not further limit the structure of the claimed kit.
Regarding claim 68, 77, 84, and 90-92, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1 from residues 36 to 478 (OA Appendix A). Thus, Bookbinder teaches C- and N-terminal truncations of PH20 that include the instant SEQ ID NO: 1. Bookbinder also teaches that the 36-478 fragment of recombinant human hyaluronidase (rHuPH20) is both soluble and active (Bookbinder claim 7). Bookbinder teaches that C-terminal truncations of PH20 are secreted proteins (liens 18-20 of column 26). Bookbinder’s SEQ ID NO: 1 is recombinant human hyaluronidase PH20 (lines 59-62 of column 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use any one of the N- and C-terminal truncations of PH20 taught by Bookbinder in the combination of claims 1-2, 40, 46, and 60 of ‘189E modified by Baert and Bookbinder. The person of ordinary skill in the art would have been motivated by Bookbinder’s teaching that these fragments, including amino acid residues 36-478, retain catalytic activity while having improved solubility (Bookbinder claim 7 and liens 18-20 of column 26).
Regarding claims 70-71, it would have been obvious to the person of ordinary skill in the art to routinely optimize the injection protocol in the method of claims 1-2, 40, 46, and 60 of ‘189E modified by Baert and Bookbinder in order to optimize the pharmacokinetic profile of rilpivirine in vivo. The person of ordinary skill in the art would have envisaged a finite number of options for delivery of the compounds (simultaneously and sequentially) and the person of ordinary skill in the art would have had a reasonable expectation of success in either option. In the case of sequential injection, the person of ordinary skill in the art would have been motivated to first inject the hyaluronidase in order to open channels in the interstitial space through degradation of glycosaminoglycans (Bookbinder column 8, lines 2-5) and subsequently inject Baert’s rilpivirine nanoparticle suspension such that the nanoparticles would have diffused through the open channels.
Regarding claim 72, 79, and 86, Baert’s nanoparticles are formulated as nanocrystals with poloxamer 338 as a surfactant (Abstract, page 503, left column “2.1. Test compounds and formulations” paragraph 2). The drug (rilpivirine) is thinly coated with the surface modifier poloxamer 338 (i.e. adsorbed), as evidenced by Elan’s NanoCrystals™ (page 2, first paragraph after second image).
Regarding claim 73, 80, and 87, the specification defines "average effective particle size" as the volume-based median particle diameter: the diameter below which 50% by volume of the particle population is found (specification page 12, lines 1-3).
Baert teaches that the particle size of the nanoparticles is less than 1 micron (200 nm, 400 nm, and 800 nm; see Abstract), but Baert does not teach the average effective particle size. Baert’s particle size is the mean volume diameter of the particles (page 503, right column, 2.2. Particle size determination and stability testing, paragraph 1).
However, since Baert is capable of producing three discrete particle sizes, all less than 1 micron, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the particle size distribution of the nanoparticles. The person of ordinary skill in the art would have had a reasonable expectation of success given that Baert already tests the production three different sizes, each of which is less than 1 micron.
Regarding claim 74, claims 1-2, 40, 46, and 60 of ‘189E do not recite administering the rilpivirine nanoparticle suspensions for the treatment HIV-1 in particular.
Baert teaches the development of a long-acting injectable formulation with nanoparticles of rilpivirine for HIV treatment. See Title and the paragraph bridging page 502 with page 503. Baert’s disclosure does not limit HIV treatment to any HIV subtype; and thus, would necessarily include treatment of HIV-1 infection. Baert also teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine nanoparticle suspension in combination with hyaluronidase in order to specifically treat HIV-1 infection in the method of claims 1-2, 40, 46, and 60 of ‘189E modified by Baert and Bookbinder. The person of ordinary skill in the art would have had a reasonable expectation of success given that rilpivirine has known therapeutic efficacy against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
Regarding claims 75, 82, and 89, Baert prepares nanoparticles from rilpivirine in its form as a free base (page 503, 2.1 Test compounds and formulations, paragraph 1).
Regarding claim 81, treatment of HIV-1 is an intended use of the product that the does not further limit the structure of the claimed product.
Regarding claim 88, treatment of HIV-1 does not further limit the structure of the claimed kit.
Claim 67-92 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 of U.S. Patent No. 10,953,009 (‘009) in view of Baert et al. (European Journal of Pharmaceutics and Biopharmaceutics 72.3 (2009): 502-508) and Bookbinder (US 7,767,429 B2), as evidenced by Locke et al. (Drug delivery 26.1 (2019): 98-106) and by Elan’s NanoCrystals (2000, website).
Claim 67 is interpreted as requiring that the release of rilpivirine from the nanoparticles is non-zero during the duration of the time interval.
Claim 1 of ‘009 recites a method of treating HIV in a subject comprising administering to the subject a solution comprising TMC278 and a carrier, wherein the solution is administered intermittently by subcutaneous or intramuscular administration at a time interval that is once every one month or once every four weeks and wherein the amount of TMC278 is effective in keeping a human blood plasma level of TMC278 in the subject during the time interval.
Claim 2 of ‘009 recites that the solution is administered intramuscularly.
Claims 1-2 of ‘009 do not recite that TMC278 (synonym for rilpivirine) is in the form of micro- or nanoparticles in suspension or that TMC278 is administered with a hyaluronidase.
Baert teaches a method of administering rilpivirine in the form of micro- or nanoparticles in suspension by intramuscular or subcutaneous injection to beagle dogs (Abstract, Figure 3, Table 2). Baert teaches that rilpivirine is a candidate for long-acting therapeutic and prophylactic treatment for HIV (page 502, right column, bottom paragraph). Baert teaches that the nanoparticles maintain rilpivirine plasma concentrations above 5 ng/mL for at least three months (Fig. 3), thus Baert teaches “prolonged, extended, sustained release of rilpivirine in blood plasma.” Baert teaches the mean plasma concentration profiles of rilpivirine nanosuspensions in beagle dogs after subcutaneous dosing of 400 and 800 nm nanosuspensions at 5 or 20 mg/kg (Fig. 3). Baert teaches that plasma concentrations exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate TMC278 (rilpivirine) as nanoparticles in the method of claims 1-2 of ‘009 such that the TMC278 formulation would have sustained plasma concentrations over a longer time interval. The person of ordinary skill in the art would have been motivated by the teaching of Baert, which suggests that nanoparticles of TMC278 are effective in maintaining plasma concentrations above 5 ng/mL for at least three months (Fig. 3). The person of ordinary skill in the art would have had a reasonable expectation of success in both the nanoparticle TMC278 formulation and the longer time interval between intermittent administrations of the formulation.
Bookbinder teaches that subcutaneous administration of molecules in the presence of a hyaluronidase facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that hyaluronidase opens channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size. (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the TMC278 (rilpivirine) nanoparticle suspension of claims 1-2 of ’009 modified by Baert with the hyaluronidase enzyme of Bookbinder and to administer the combination to a subject in order to treat HIV infection. The person of ordinary skill in the art would have been motivated to enhance systemic distribution of the rilpivirine. One of ordinary skill would have had a reasonable expectation of success given the teaching of Bookbinder that hyaluronidase enzyme facilitates the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they are less than 500 nm in size. Because the nanoparticles of Baert are on the order of 200 nm or 400 nm (Abstract), which is less than the 500 nm size limit taught by Bookbinder, the person of ordinary skill in the art would have had a reasonable expectation of success in enhanced diffusion of rilpivirine nanoparticles.
Regarding the time interval for administration in claim 67 (“wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years”) and claim 69 (“wherein the time interval is about three months to about six months”), claims 1-2 of ‘009 do not recite that the time interval is about three months.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to increase the time interval for the administration of rilpivirine nanoparticle suspensions and hyaluronidase in order to optimize the pharmacokinetic profile of rilpivirine in vivo. The person of ordinary skill in the art would have had a reasonable expectation of success given that Fig. 3 of Baert teaches that the plasma concentration exceeds 5 ng/mL for three months. In addition, administering rilpivirine in combination with a hyaluronidase would have been expected to enhance the delivery of rilpivirine into interstitial spaces, thus increasing the plasma concentration and increasing the area under the curve as evidenced by Locke et al. (page 98, right column, lines 1-3).
Regarding claim 76, claims 1-2 of ‘009 do not recite and Baert does not teach that rilpivirine in the form of nanoparticles in suspension is a combined preparation with hyaluronidase.
However, as discussed above with respect to claim 67 and its dependents, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine and hyaluronidase for the treatment of HIV, thus a combined preparation of rilpivirine and hyaluronidase would also have been obvious.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 76) and “wherein the time interval is about three months to about six months (claim 78), these limitations pertain to an intended use of the preparation and do not further limit the structure of the claimed product.
Regarding claim 83, claims 1-2, of ‘009 do not recite and Baert does not teach a kit comprising a rilpivirine in the form of nanoparticles in suspension and a hyaluronidase.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the rilpivirine of claims 1-2, 40, 46, and 60 of ‘189E modified by Baert as a nanoparticle suspension together with Bookbinder’s hyaluronidase in a kit for commercial use. The person of ordinary skill in the art would have been motivated to facilitate performing a method of treatment of HIV infection by medical professionals or patients. The person of ordinary skill in the art would have had a reasonable expectation of success in this endeavor.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 83) and “wherein the time interval is about three months to about six months” (claim 85), these limitations pertain to an intended use of the kit and do not further limit the structure of the claimed kit.
Regarding claim 68, 77, 84, and 90-92, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1 from residues 36 to 478 (OA Appendix A). Thus, Bookbinder teaches C- and N-terminal truncations of PH20 that include the instant SEQ ID NO: 1. Bookbinder also teaches that the 36-478 fragment of recombinant human hyaluronidase (rHuPH20) is both soluble and active (Bookbinder claim 7). Bookbinder teaches that C-terminal truncations of PH20 are secreted proteins (liens 18-20 of column 26). Bookbinder’s SEQ ID NO: 1 is recombinant human hyaluronidase PH20 (lines 59-62 of column 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use any one of the N- and C-terminal truncations of PH20 taught by Bookbinder in the method of claims 1-2 of ‘009 modified by Baert and Bookbinder. The person of ordinary skill in the art would have been motivated by Bookbinder’s teaching that these fragments, including amino acid residues 36-478, retain catalytic activity while having improved solubility (Bookbinder claim 7 and liens 18-20 of column 26).
Regarding claims 70-71, it would have been obvious to the person of ordinary skill in the art to routinely optimize the injection protocol in the method of claims 1-2, of ‘009 modified by Baert and Bookbinder in order to optimize the pharmacokinetic profile of rilpivirine in vivo. The person of ordinary skill in the art would have envisaged a finite number of options for delivery of the compounds (simultaneously and sequentially) and the person of ordinary skill in the art would have had a reasonable expectation of success in either option. In the case of sequential injection, the person of ordinary skill in the art would have been motivated to first inject the hyaluronidase in order to open channels in the interstitial space through degradation of glycosaminoglycans (Bookbinder column 8, lines 2-5) and subsequently inject Baert’s rilpivirine nanoparticle suspension such that the nanoparticles would have diffused through the open channels.
Regarding claim 72, 79, and 86, Baert’s nanoparticles are formulated as nanocrystals with poloxamer 338 as a surfactant (Abstract, page 503, left column “2.1. Test compounds and formulations” paragraph 2). The drug (rilpivirine) is thinly coated with the surface modifier poloxamer 338 (i.e. adsorbed), as evidenced by Elan’s NanoCrystals™ (page 2, first paragraph after second image).
Regarding claim 73, 80, and 87, the specification defines "average effective particle size" as the volume-based median particle diameter: the diameter below which 50% by volume of the particle population is found (specification page 12, lines 1-3).
Baert teaches that the particle size of the nanoparticles is less than 1 micron (200 nm, 400 nm, and 800 nm; see Abstract), but Baert does not teach the average effective particle size. Baert’s particle size is the mean volume diameter of the particles (page 503, right column, 2.2. Particle size determination and stability testing, paragraph 1).
However, since Baert is capable of producing three discrete particle sizes, all less than 1 micron, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the particle size distribution of the nanoparticles. The person of ordinary skill in the art would have had a reasonable expectation of success given that Baert already tests the production three different sizes, each of which is less than 1 micron.
Regarding claim 74, claims 1-2 of ‘009 do not recite administering the rilpivirine nanoparticle suspensions for the treatment of HIV-1 in particular.
Baert teaches the development of a long-acting injectable formulation with nanoparticles of rilpivirine for HIV treatment. See Title and the paragraph bridging page 502 with page 503. Baert’s disclosure does not limit HIV treatment to any HIV subtype; and thus, would necessarily include treatment of HIV-1 infection. Baert also teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine nanoparticle suspension in combination with hyaluronidase in order to specifically treat HIV-1 infection in the method of claims 1-2 of ‘009 modified by Baert and Bookbinder. The person of ordinary skill in the art would have had a reasonable expectation of success given that rilpivirine has known therapeutic efficacy against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
Regarding claim 75, 82, and 89, Baert prepares nanoparticles from rilpivirine in its form as a free base (page 503, 2.1 Test compounds and formulations, paragraph 1).
Regarding claim 81, treatment of HIV-1 is an intended use of the product that the does not further limit the structure of the claimed product.
Regarding claim 88, treatment of HIV-1 does not further limit the structure of the claimed kit.
Claims 67-92 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-37 of copending Application No. 18/897636 (hereafter ‘636) in view of Baert and Bookbinder as evidenced by Locke and Elan’s NanoCrystals.
Claim 67 is interpreted as requiring that the release of rilpivirine from the nanoparticles is non-zero during the duration of the time interval.
Instant claims 67-89 require rilpivirine, which is a synonym for TMC278. E-TMC28 (E stereoisomer) is a species of TMC278 (racemic mixture of stereoisomers).
Claim 1 of ‘636 is drawn to a method of treating HIV in a subject comprising administering to the subject a solution comprising TMC278, wherein the solution is administered intermittently by subcutaneous or intramuscular administration at a time interval that is once every one month or once every four weeks, and wherein the amount of TMC278 is effective in keeping a minimum blood plasma level of TMC278 in the subject during the time interval. Claims 2-13 of ‘636 depend from claim 1.
Claim 14 of ‘636 is drawn to a method of treating HIV infection in a subject comprising administering to the subject an aqueous parenteral formulation comprising 600 mg of E-TMC278 in its base form and a carrier, wherein the aqueous parenteral formulation is administered by single intramuscular injection every month or four weeks, wherein the subject’s blood plasma level of E-TMC278 between administrations is maintained above 13.5 ng/ml. Claims 15-25 of ‘636 depend from claim 14.
Claim 26 of ‘636 is drawn to a method of treating HIV infection in a subject comprising administering to the subject an aqueous parenteral formulation comprising an amount of E-TMC278 and a carrier, wherein the aqueous parenteral formulation is administered by a single intramuscular injection once every two months, wherein the amount of E-TMC278 is a dose calculated on a basis of about 10 mg/day to about 20 mg/day of the time interval between administrations, and wherein the subject’s blood plasma level of E-TMC28 between administrations is maintained above 13.5 ng/ml. Claims 27-37 of ‘636 depend from claim 26.
Claims 1-37 of ‘636 do not recite that TMC278 is administered in the form of a nanoparticle suspension with a hyaluronidase.
Baert teaches a method of administering rilpivirine in the form of micro- or nanoparticles in suspension by intramuscular or subcutaneous injection to beagle dogs (Abstract, Figure 3, Table 2). Baert teaches that rilpivirine is a candidate for long-acting therapeutic and prophylactic treatment for HIV (page 502, right column, bottom paragraph). Baert teaches that the nanoparticles maintain rilpivirine plasma concentrations above 5 ng/mL for at least three months (Fig. 3), thus Baert teaches “prolonged, extended, sustained release of rilpivirine in blood plasma.” Baert teaches the mean plasma concentration profiles of rilpivirine nanosuspensions in beagle dogs after subcutaneous dosing of 400 and 800 nm nanosuspensions at 5 or 20 mg/kg (Fig. 3). Baert teaches that plasma concentrations exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate TMC278 (rilpivirine) or E-TMC278 (E-stereoisomer of rilpivirine) as nanoparticles in suspension in the method of claims 1-37 of ‘636 such that the TMC278 formulation would have sustained plasma concentrations over a longer time interval. The person of ordinary skill in the art would have been motivated by the teaching of Baert, which suggests that nanoparticles of TMC278 are effective in maintaining plasma concentrations above 5 ng/mL for at least three months (Fig. 3). The person of ordinary skill in the art would have had a reasonable expectation of success in both the nanoparticle TMC278 formulation and the longer time interval between intermittent administrations of the formulation.
Bookbinder teaches that subcutaneous administration of molecules in the presence of a hyaluronidase facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that hyaluronidase opens channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the TMC278 (rilpivirine) nanoparticle suspension of claims 1-37 of ‘636 modified by Baert with the hyaluronidase enzyme of Bookbinder and to administer the combination to a subject in order to treat HIV infection. The person of ordinary skill in the art would have been motivated to enhance systemic distribution of the rilpivirine. One of ordinary skill would have had a reasonable expectation of success given the teaching of Bookbinder that hyaluronidase facilitates the diffusion of many forms of therapeutic molecules and proteins, including small molecules, proteins, and nucleic acids, as long as they are less than 500 nm in size. Because the nanoparticles of Baert are on the order of 200 nm or 400 nm (Abstract), which is less than the 500 nm size limit taught by Bookbinder, the person of ordinary skill in the art would have had a reasonable expectation of success in enhanced diffusion of rilpivirine nanoparticles.
Regarding the time interval for administration in claim 67 (“wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years”) and claim 69, Baert teaches that plasma concentrations exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4). The plasma concentration in subjects administered 20 mg/kg of rilpivirine in 400 nm nanoparticle suspensions is about 15 ng/mL after 42 days (Figure 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the timing of the delivery of the combination of rilpivirine nanoparticle suspensions and hyaluronidase in order to optimize the pharmacokinetic profile of rilpivirine in vivo in the method of claims 1-37 of ‘636 modified by Baert and Bookbinder. The person of ordinary skill in the art would have had a reasonable expectation of success given that the plasma concentration was already near the theoretical optimum of 20 ng/ml after 42 days. Furthermore, administration of hyaluronidase in combination with the rilpivirine nanoparticle suspensions would have been expected to increase the bioavailability of rilpivirine, thus increasing the area under the curve (AUC), as evidenced by Locke (page 98, right column, lines 1-3).
Regarding claim 76, claims 1-37 of ‘636 do not recite and Baert does not teach that rilpivirine in the form of nanoparticles in suspension is a combined preparation with hyaluronidase.
However, as discussed above with respect to claim 67 and its dependents, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine and hyaluronidase for the treatment of HIV, thus a combined preparation of rilpivirine and hyaluronidase would also have been obvious.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 76) and “wherein the time interval is about three months to about six months (claim 78), these limitations pertain to an intended use of the preparation and do not further limit the structure of the claimed product.
Regarding claim 83, claims 1-37 of ‘636 do not recite and Baert does not teach a kit comprising a rilpivirine in the form of nanoparticles in suspension and a hyaluronidase.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the rilpivirine in the method of claims 1-37 of ‘636 as nanoparticle suspensions per Baert together with Bookbinder’s hyaluronidase in a kit for commercial use. The person of ordinary skill in the art would have been motivated to facilitate performing a method of treatment of HIV infection by medical professionals or patients. The person of ordinary skill in the art would have had a reasonable expectation of success in this endeavor.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 83) and “wherein the time interval is about three months to about six months” (claim 85), these limitations pertain to an intended use of the kit and do not further limit the structure of the claimed kit.
Regarding claim 68, 77, 84, and 90-92, Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1 from residues 36 to 478 (OA Appendix A). Thus, Bookbinder teaches C- and N-terminal truncations of PH20 that include the instant SEQ ID NO: 1. Bookbinder also teaches that the 36-478 fragment of recombinant human hyaluronidase (rHuPH20) is both soluble and active (Bookbinder claim 7). Bookbinder teaches that C-terminal truncations of PH20 are secreted proteins (liens 18-20 of column 26). Bookbinder’s SEQ ID NO: 1 is recombinant human hyaluronidase PH20 (lines 59-62 of column 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use any one of the N- and C-terminal truncations of PH20 taught by Bookbinder in the combination of claims 1-37 of ‘636 modified by Baert and Bookbinder. The person of ordinary skill in the art would have been motivated by Bookbinder’s teaching that these fragments, including 36-478, retain catalytic activity while having improved solubility (Bookbinder claim 7 and liens 18-20 of column 26).
Regarding claims 70-71, it would have been obvious to the person of ordinary skill in the art to routinely optimize the injection protocol of the Baert’s rilpivirine nanoparticle suspension with Bookbinder’s hyaluronidase in order to optimize the pharmacokinetic profile of rilpivirine in vivo. The person of ordinary skill in the art would have envisaged a finite number of options for delivery of the compounds (simultaneously and sequentially) and the person of ordinary skill in the art would have had a reasonable expectation of success in either option. In the case of sequential injection, the person of ordinary skill in the art would have been motivated to first inject the hyaluronidase in order to open channels in the interstitial space through degradation of glycosaminoglycans (Bookbinder column 8, lines 2-5) and subsequently inject Baert’s rilpivirine nanoparticle suspension such that the nanoparticles would have diffused through the open channels.
Regarding claim 72, 79, and 86, claims 16 and 28 of ‘636 recite that the aqueous parenteral formulation further comprises poloxamer 338. Baert’s nanoparticles are formulated as nanocrystals with poloxamer 338 as a surfactant (Abstract, page 503, left column “2.1. Test compounds and formulations” paragraph 2). The drug (rilpivirine) is thinly coated with the surface modifier poloxamer 338 (i.e. adsorbed), as evidenced by Elan’s NanoCrystals™ (page 2, first paragraph after second image).
Regarding claim 73, 80, and 87, the specification defines "average effective particle size" as the volume-based median particle diameter: the diameter below which 50% by volume of the particle population is found (specification page 12, lines 1-3).
Baert teaches that the particle size of the nanoparticles is less than 1 micron (200 nm, 400 nm, and 800 nm; see Abstract), but Baert does not teach the average effective particle size. Baert’s particle size is the mean volume diameter of the particles (page 503, right column, 2.2. Particle size determination and stability testing, paragraph 1).
However, since Baert is capable of producing three discrete particle sizes, all less than 1 micron, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the particle size distribution of the nanoparticles. The person of ordinary skill in the art would have had a reasonable expectation of success given that Baert already tests the production three different sizes, each of which is less than 1 micron.
Regarding claim 74, claims 1-37 of ‘636 do not recite administering rilpivirine to treat specifically HIV-1 in particular.
Baert teaches the development of a long-acting injectable formulation with nanoparticles of rilpivirine for HIV treatment. See Title and the paragraph bridging page 502 with page 503. Baert’s disclosure does not limit HIV treatment to any HIV subtype; and thus, would necessarily include treatment of HIV-1 infection. Baert also teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine nanoparticle suspension in combination with hyaluronidase in order to specifically treat HIV-1 infection in the method of claims 1-37 of ‘636. The person of ordinary skill in the art would have had a reasonable expectation of success given that rilpivirine has known therapeutic efficacy against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
Regarding claim 75, 82, and 89, Baert prepares nanoparticles from rilpivirine in its form as a free base (page 503, 2.1 Test compounds and formulations, paragraph 1).
Regarding claim 81, treatment of HIV-1 is an intended use of the product that the does not further limit the structure of the claimed product.
Regarding claim 88, treatment of HIV-1 does not further limit the structure of the claimed kit.
This is a provisional nonstatutory double patenting rejection.
Claims 67-70, 72-75, 83-90, and 92 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 15-16, 28-30, 39-40, and 68-72 of copending Application No. 18/858,242 (hereafter ‘242) in view of Baert and Bookbinder as evidenced by Locke and Elan’s NanoCrystals.
Claim 67 is interpreted as requiring that the release of rilpivirine from the nanoparticles is non-zero during the duration of the time interval.
Claim 1 of ‘242 recites an aqueous composition comprising rilpivirine or a pharmaceutically acceptable salt thereof, a hyaluronidase, and an excipient.
Claim 2 of ‘242 recites that rilpivirine is in the form of particles suspended in the aqueous composition.
Claim 3 of ‘242 recites that the rilpivirine is in the form of microparticles or nanoparticles suspended in the aqueous composition.
Claim 4 of ‘242 recites that the hyaluronidase is rHuPH20.
Claims 5-7, 15-16, 28-30, and 39-40 of ‘242 further limit the composition of claim 1.
Claim 68 of ‘242 recites an aqueous composition comprising rilpivirine and an excipient. Claims 69-72 of ‘242 further limit the composition of claim 68. Claim 70 of ‘242 recites that the composition further comprises a poloxamer.
Claims 1-7, 15-16, 28-30, 39-40, and 68-72 of ‘242 do not recite that the composition is administered by intramuscular or subcutaneous injection to treat HIV, wherein the rilpivirine and hyaluronidase are administered intermittently at a time interval of about three months to about two years.
Baert teaches a method of administering rilpivirine in the form of micro- or nanoparticles in suspension by intramuscular or subcutaneous injection to beagle dogs (Abstract, Figure 3, Table 2). Baert teaches that rilpivirine is a candidate for long-acting therapeutic and prophylactic treatment for HIV (page 502, right column, bottom paragraph). Baert teaches that the nanoparticles maintain rilpivirine plasma concentrations above 5 ng/mL for at least three months (Fig. 3), thus Baert teaches “prolonged, extended, sustained release of rilpivirine in blood plasma.” Baert teaches the mean plasma concentration profiles of rilpivirine nanosuspensions in beagle dogs after subcutaneous dosing of 400 and 800 nm nanosuspensions at 5 or 20 mg/kg (Fig. 3). Baert teaches that plasma concentrations exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4). The mean exposure over a three-month period amounted to 41.4 µg h/mL after intramuscular administration and 24.4 µg h/mL after SC administration (page 506, left column, 3.2.2. Impact of administration route, paragraph 2).
In addition, Baert teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains and its potent antiviral effect has been confirmed in a dose-finding study in treatment-naïve HIV patients (paragraph bridging pages 502-503). Therefore, Baert teaches “a subject tin need thereof”) (the HIV patients).
Bookbinder teaches that subcutaneous administration of molecules in the presence of a hyaluronidase facilitates their rapid systemic distribution (column 8, lines 30-33). Bookbinder teaches that hyaluronidase opens channels in the interstitial space through degradation of glycosaminoglycans (column 8, lines 2-5) and that these channels facilitate the diffusion of small molecules, proteins, and nucleic acids less than 500 nm in size (column 8, lines 6-10). Bookbinder teaches further that temporary removal of glycosaminoglycans enhances the delivery of drugs into interstitial spaces, which facilitates diffusion of therapeutic molecules and proteins (column 8, lines 26-30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to intramuscularly or subcutaneously administer the composition of claims 1-7, 15-16, 28-30, and 39-40 of ‘242 for the treatment of HIV. The person of ordinary skill in the art would have been motivated by the teaching of Baert, which suggests that rilpivirine is effective in treating HIV and Bookbinder, which suggests that hyaluronidase facilitates the diffusion of molecules. Similarly, it would have been obvious to combine Bookbinder’s hyaluronidase with the composition of claims 68-72 of ‘242 and to administer the composition intramuscularly or subcutaneously to treat HIV.
Regarding the time interval for administration in claim 67 (“wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years”) and claim 69, Baert teaches that plasma concentrations of rilpivirine exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4). The plasma concentration in subjects administered 20 mg/kg of rilpivirine in 400 nm nanoparticle suspensions is about 15 ng/mL after 42 days (Figure 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the timing of the delivery of the composition of claims 1-7, 15-16, 28-30, 39-40, and 68-72 of ‘242 modified by Baert and Bookbinder in order to optimize the pharmacokinetic profile of rilpivirine. The person of ordinary skill in the art would have had a reasonable expectation of success given that the plasma concentration was already near the theoretical optimum of 20 ng/ml after 42 days. Furthermore, administration of hyaluronidase in combination with the rilpivirine nanoparticle suspensions would have been expected to increase the bioavailability of rilpivirine, thus increasing the area under the curve (AUC), as evidenced by Locke (page 98, right column, lines 1-3),
Regarding claim 83, claims 1-7, 15-16, 28-30, 39-40, and 68-72 of ‘242 do not recite and Baert and Bookbinder do not teach a kit comprising rilpivirine in the form of nanoparticles in suspension and a hyaluronidase.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the composition of claims 1-7, 15-16, 28-30, 39-40, and 68-72 of ‘242 modified by Baert and Bookbinder as a kit for commercial use. The person of ordinary skill in the art would have been motivated to facilitate performing a method of treatment of HIV infection by medical professionals or patients. The person of ordinary skill in the art would have had a reasonable expectation of success in this endeavor.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 83) and “wherein the time interval is about three months to about six months” (claim 85), these limitations pertain to an intended use of the kit and do not further limit the structure of the claimed kit.
Regarding claims 68, 84, 90, and 92 Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1 from residues 36 to 478 (OA Appendix A). Thus, Bookbinder teaches C- and N-terminal truncations of PH20 that include the instant SEQ ID NO: 1. Bookbinder also teaches that the 36-478 fragment of recombinant human hyaluronidase (rHuPH20) is both soluble and active (Bookbinder claim 7). Bookbinder teaches that C-terminal truncations of PH20 are secreted proteins (liens 18-20 of column 26). Bookbinder’s SEQ ID NO: 1 is recombinant human hyaluronidase PH20 (lines 59-62 of column 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use any one of the N- and C-terminal truncations of PH20 taught by Bookbinder in the combination of claims 1-7, 15-16, 28-30, 39-40, and 68-72 of ‘242 modified by Baert and Bookbinder. The person of ordinary skill in the art would have been motivated by Bookbinder’s teaching that these fragments, including amino acid residues 36-478, retain catalytic activity while having improved solubility (Bookbinder claim 7 and liens 18-20 of column 26).
Regarding claim 70, administering the composition of claims 1-7, 15-16, 28-30, 39-40 of ‘242 would have necessarily simultaneously administered the rilpivirine with the hyaluronidase.
Regarding claims 72 and 86, claims 1-7, 15-16, 28-30, 39-40 of ‘242 do not recite that the aqueous parenteral formulation further comprises poloxamer 338. Baert’s nanoparticles are formulated as nanocrystals with poloxamer 338 as a surfactant (Abstract, page 503, left column “2.1. Test compounds and formulations” paragraph 2). The drug (rilpivirine) is thinly coated with the surface modifier poloxamer 338 (i.e. adsorbed), as evidenced by Elan’s NanoCrystals™ (page 2, first paragraph after second image).
Regarding claims 73 and 87, the specification defines "average effective particle size" as the volume-based median particle diameter: the diameter below which 50% by volume of the particle population is found (specification page 12, lines 1-3).
Baert teaches that the particle size of the nanoparticles is less than 1 micron (200 nm, 400 nm, and 800 nm; see Abstract), but Baert does not teach the average effective particle size. Baert’s particle size is the mean volume diameter of the particles (page 503, right column, 2.2. Particle size determination and stability testing, paragraph 1).
However, since Baert is capable of producing three discrete particle sizes, all less than 1 micron, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the particle size distribution of the nanoparticles. The person of ordinary skill in the art would have had a reasonable expectation of success given that Baert already tests the production three different sizes, each of which is less than 1 micron.
Regarding claim 74, claims 1-7, 15-16, 28-30, 39-40 and 68-72 of ‘242 do not recite administering rilpivirine to treat specifically HIV-1.
Baert teaches the development of a long-acting injectable formulation with nanoparticles of rilpivirine for HIV treatment. See Title and the paragraph bridging page 502 with page 503. Baert’s disclosure does not limit HIV treatment to any HIV subtype; and thus, would necessarily include treatment of HIV-1 infection. Baert also teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine and hyaluronidase in the composition of claims 1-7, 15-16, 28-30, 39-40, and 68-72 of ‘242 modified by Baert and Bookbinder in order to specifically treat HIV-1 infection. The person of ordinary skill in the art would have had a reasonable expectation of success given that rilpivirine has known therapeutic efficacy against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
Regarding claims 75 and 89, claims 1-7, 15-16, 28-30, 39-40 and 68-72 of ‘242 recite “rilpivirine or a pharmaceutically acceptable salt thereof,” so in one embodiment, rilpivirine is not a salt.
Regarding claim 88, treatment of HIV-1 does not further limit the structure of the claimed kit.
This is a provisional nonstatutory double patenting rejection.
Claims 76, 78, and 81-82 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 18/858,242 (hereafter ‘242). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 76, 78, and 81-82 are anticipated by claim 3 of ‘242.
See above for the recitation of claims 1-7, 15-16, 28-30, and 39-40 of ‘242, which is incorporated into this rejection as well.
Instant claims 76 and 78 are anticipated by claim 3 of ‘242. This rejection applies to the embodiment in which the intended use is simultaneous use in the treatment of HIV infection.
Regarding the limitations “wherein the combined preparation rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (instant claim 76) and “wherein the time interval is about three months to about six months (instant claim 78), these limitations pertain to an intended use of the preparation and do not further limit the structure of the claimed product. Likewise, “wherein a prolonged, extended, sustained release of rilpivirine or a pharmaceutically acceptable salt thereof into the blood plasma is maintained” is an intended use of the product and does not further limit the structure of the claimed product.
Regarding instant claim 81, treatment of HIV-1 is an intended use of the product that the does not further limit the structure of the claimed product.
Regarding instant claim 82, claim 3 of ‘242 recites rilpivirine is in the form of microparticles or nanoparticles suspended in the aqueous composition, so rilpivirine is not a salt.
This is a provisional nonstatutory double patenting rejection.
Claims 77 and 91 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 18/858,242 (hereafter ‘242) in view of Bookbinder.
See discussion of claim 3 of ‘242 above, which is incorporated into this rejection as well.
Claim 3 of ‘242 does not recite that the hyaluronidase is rHuPH20 comprising SEQ ID NO: 1.
Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1 from residues 36 to 478 (OA Appendix A). Thus, Bookbinder teaches C- and N-terminal truncations of PH20 that include the instant SEQ ID NO: 1. Bookbinder also teaches that the 36-478 fragment of recombinant human hyaluronidase (rHuPH20) is both soluble and active (Bookbinder claim 7). Bookbinder teaches that C-terminal truncations of PH20 are secreted proteins (lines 18-20 of column 26). Bookbinder’s SEQ ID NO: 1 is recombinant human hyaluronidase PH20 (lines 59-62 of column 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use any one of the N- and C-terminal truncations of PH20 taught by Bookbinder in the composition of claim 3 of ‘242. The person of ordinary skill in the art would have been motivated by Bookbinder’s teaching that these fragments, including amino acid residues 36-478 of SEQ ID NO: 1, retain catalytic activity while having improved solubility (Bookbinder claim 7 and liens 18-20 of column 26).
This is a provisional nonstatutory double patenting rejection.
Claims 79-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 18/858,242 (hereafter ‘242) in view of Baert as evidenced by Elan’s NanoCrystals.
See above recitation of claim 3 of ‘212.
Claim 3 of ‘212 does not recite that the nanoparticles have poloxamer adsorbed to their surface (instant claim 79) or that the average effective particle size of
the micro- or nanoparticles is less than about 1 micron. (instant claim 80).
Baert teaches rilpivirine nanoparticles formulated as nanocrystals with poloxamer 338 as a surfactant (Abstract, page 503, left column “2.1. Test compounds and formulations” paragraph 2). The drug (rilpivirine) is thinly coated with the surface modifier poloxamer 338 (i.e. adsorbed) to impart physical stability, as evidenced by Elan’s NanoCrystals™ (page 2, first paragraph after second image).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Baert’s technique to formulate the rilpivirine nanoparticles in the composition of claim 3 of ‘242 and the person of ordinary skill in the art would have had a reasonable expectation of success in doing so.
Regarding instant claim 80, Baert teaches that the particle size of the nanoparticles is less than 1 micron (200 nm, 400 nm, and 800 nm; see Abstract), but Baert does not teach the average effective particle size. Baert’s particle size is the mean volume diameter of the particles (page 503, right column, 2.2. Particle size determination and stability testing, paragraph 1).
However, since Baert is capable of producing three discrete particle sizes, all less than 1 micron, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the particle size distribution of the nanoparticles. The person of ordinary skill in the art would have had a reasonable expectation of success given that Baert already tests the production of three different sizes, each of which is less than 1 micron.
This is a provisional nonstatutory double patenting rejection.
Claims 67-70, 72-75, 83-89, 90, and 92 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of copending Application No. 18/858,037 (‘037) in view of Baert as evidenced by Locke, Bookbinder, and Elan’s NanoCrystals.
Claim 67 is interpreted as requiring that the release of rilpivirine from the nanoparticles is non-zero during the duration of the time interval.
Claims 1-13 and 16 of ‘037 are drawn to a solid composition obtainable by freeze-drying an aqueous composition comprising rilpivirine or a pharmaceutically acceptable salt thereof and a hyaluronidase.
Claim 2 of ‘037 recites that the hyaluronidase is rHuPH20.
Claim 3 of ‘037 recites that the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, optionally wherein the particles are micro- or nanoparticles suspended in the aqueous composition.
Claim 14 of ‘037 is drawn to a reconstituted aqueous composition obtainable by reconstituting the solid composition as defined in claim 1 with an aqueous dispersion medium.
Claim 15 of ‘037 is drawn to a method of treatment or prevention of HIV infection in a subject, the method comprising administering to the subject a reconstituted aqueous composition as defined in claim 14.
Claim 15 of ‘037 does not recite that rilpivirine is administered in the form of a nanoparticle suspension to treat HIV. However, claim 3 of ‘037 recites the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, optionally wherein the particles are micro- or nanoparticles suspended in the aqueous composition.
Baert teaches a method of administering rilpivirine in the form of micro- or nanoparticles in suspension by intramuscular or subcutaneous injection to beagle dogs (Abstract, Figure 3, Table 2). Baert teaches that rilpivirine is a candidate for long-acting therapeutic and prophylactic treatment for HIV (page 502, right column, bottom paragraph). Baert teaches that the nanoparticles maintain rilpivirine plasma concentrations above 5 ng/mL for at least three months (Fig. 3), thus Baert teaches “prolonged, extended, sustained release of rilpivirine in blood plasma.” Baert teaches the mean plasma concentration profiles of rilpivirine nanosuspensions in beagle dogs after subcutaneous dosing of 400 and 800 nm nanosuspensions at 5 or 20 mg/kg (Fig. 3). Baert teaches that plasma concentrations exceeding 20 ng/mL are therapeutically effective in theory (page 507, right column, paragraph 4).
In addition, Baert teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains and its potent antiviral effect has been confirmed in a dose-finding study in treatment-naïve HIV patients (paragraph bridging pages 502-503). Therefore, Baert teaches “a subject tin need thereof”) (the HIV patients).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to reconstitute the solid composition of claim 3 of ‘037 and to administer the composition to a subject in order to treat HIV. Likewise it would have been obvious to formulate rilpivirine as a nanoparticle suspension in any of the solid compositions of claims 1-13 and 16 of ‘037, reconstitute the solid composition (claim 14 of ‘037), and to administer the composition to a subject to treat HIV (claim 15 of ‘037). The person of ordinary skill in the art would have had a reasonable expectation of success in administering the composition comprising rilpivirine in the form of a nanoparticle suspension in combination with hyaluronidase.
Regarding the time interval for administration in instant claim 67 (“wherein the rilpivirine or a pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years”) and claim 69, Baert teaches that the plasma concentration in subjects administered 20 mg/kg of rilpivirine in 400 nm nanoparticle suspensions is about 15 ng/mL after 42 days (Figure 3), which is approaching the theoretical lower limit for therapeutic efficacy (page 507, right column, paragraph 4).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the timing of the delivery of the combination of rilpivirine nanoparticle suspensions and hyaluronidase in order to optimize the pharmacokinetic profile of rilpivirine in vivo in the method of claims 1-16 of ‘037 modified by Baert. The person of ordinary skill in the art would have had a reasonable expectation of success given that the plasma concentration was already near the theoretical optimum of 20 ng/ml after 42 days. Furthermore, administration of hyaluronidase in combination with the rilpivirine nanoparticle suspensions would have been expected to increase the bioavailability of rilpivirine, thus increasing the area under the curve (AUC), as evidenced by Locke (page 98, right column, lines 1-3),
Regarding claim 83, claims 1-16 of ‘037 do not recite and Baert does not teach a kit comprising rilpivirine in the form of nanoparticles in suspension and a hyaluronidase.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the composition of claims 1-16 of ‘037 modified by Baert as a kit for commercial use. The person of ordinary skill in the art would have been motivated to facilitate performing a method of treatment of HIV infection by medical professionals or patients. The person of ordinary skill in the art would have had a reasonable expectation of success in this endeavor.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 83) and “wherein the time interval is about three months to about six months” (claim 85), these limitations pertain to an intended use of the kit and do not further limit the structure of the claimed kit.
Regarding claim 68, 84, 90 and 92 claims 1-16 of ‘037 do not recite that the hyaluronidase is rHuPH20 (recombinant human hyaluronidase) comprising the amino acid sequence of SEQ ID NO: 1, although claim 2 of ‘037 recites that the hyaluronidase is rHuPH20.
The amino acid sequence for PH20 comprises SEQ ID NO: 1, as evidenced by Bookbinder (see OA Appendix A alignment of the instant SEQ ID NO: 1 to Bookbinder’s SEQ ID NO: 1, which is recombinant human hyaluronidase PH20, see lines 59-62 of column 3).
Regarding claim 70, claim 15 of ‘037 recites administering the reconstituted composition comprising rilpivirine and hyaluronidase. Rilpivirine and the hyaluronidase are formulated together, so it would have been obvious to administer them simultaneously.
Regarding claim 72 and 86, claims 1-16 of ‘037 do not recite that the nanoparticles have a surface modifier adsorbed to their surface, wherein the surface modifier is poloxamer.
Baert’s nanoparticles are formulated as nanocrystals with poloxamer 338 as a surfactant (Abstract, page 503, left column “2.1. Test compounds and formulations” paragraph 2). The drug (rilpivirine) is thinly coated with the surface modifier poloxamer 338 (i.e. adsorbed) ) to impart physical stability, as evidenced by Elan’s NanoCrystals™ (page 2, first paragraph after second image).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the nanoparticles in the method of claims 1-16 of ‘037 modified by Baert with poloxamer 338 as a surfactant per the teaching of Baert. The person of ordinary skill in the art would have had a reasonable expectation in the formulation of the nanoparticles with poloxamer.
Regarding claim 73 and 87, the specification defines "average effective particle size" as the volume-based median particle diameter: the diameter below which 50% by volume of the particle population is found (specification page 12, lines 1-3).
Baert teaches that the particle size of the nanoparticles is less than 1 micron (200 nm, 400 nm, and 800 nm; see Abstract), but Baert does not teach the average effective particle size. Baert’s particle size is the mean volume diameter of the particles (page 503, right column, 2.2. Particle size determination and stability testing, paragraph 1).
However, since Baert is capable of producing three discrete particle sizes, all less than 1 micron, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the particle size distribution of the nanoparticles in the method of claims 1-16 of ‘037 modified by Baert. The person of ordinary skill in the art would have had a reasonable expectation of success given that Baert already tests the production three different sizes, each of which is less than 1 micron.
Regarding claim 74, claims 1-16 of ‘037 do not recite administering rilpivirine to treat specifically HIV-1.
Baert teaches the development of a long-acting injectable formulation with nanoparticles of rilpivirine for HIV treatment. See Title and the paragraph bridging page 502 with page 503. Baert’s disclosure does not limit HIV treatment to any HIV subtype; and thus, would necessarily include treatment of HIV-1 infection. Baert also teaches that rilpivirine is effective against a broad range of wild-type and HIV-mutant strains (Baert paragraph 1 on the left column of page 503).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to administer rilpivirine nanoparticle suspension in combination with hyaluronidase in order to specifically treat HIV-1 infection in the method of claims 1-16 of ‘037 modified by Baert. The person of ordinary skill in the art would have had a reasonable expectation of success given that rilpivirine has known therapeutic efficacy against a broad range of wild-type and HIV-mutant strains (Baert, paragraph 1 on the left column of page 503).
Regarding claim 75 and 89, claims 1-16 of ‘037 recite “rilpivirine or a pharmaceutically acceptable salt thereof.” Therefore, in one embodiment rilpivirine is not a salt.
Regarding claim 88, treatment of HIV-1 does not further limit the structure of the claimed kit.
This is a provisional nonstatutory double patenting rejection.
Claims 76, 78 and 81-82 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3 and 15 of copending Application No. 18/858,037 (‘037). Although the claims at issue are not identical, they are not patentably distinct from each other because claims 76, 78, and 81-82 are obvious over claims 3 and 14-15 of ‘037.
See above for the recitation of claims 3 and 15 of ‘037, which is incorporated into this rejection as well.
Regarding instant claim 76, claim 3 of ‘037 recites that the aqueous composition comprises rilpivirine or a pharmaceutically acceptable salt thereof in the form of particles suspended in the aqueous composition, optionally wherein the particles are micro- or nanoparticles suspended in the aqueous composition.
Claim 3 of ‘037 does not recite that the composition is reconstituted (i.e. suitable for performing the intended use of subcutaneous or intramuscular injection).
However, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to reconstitute the composition of claim 3 such that the composition could have been administered, as suggested in claim 15 of ‘037. The person of ordinary skill in the art would have had a reasonable expectation of success in the reconstitution of the composition of claim 3 of ‘037.
Regarding the limitations “wherein the rilpivirine or pharmaceutically acceptable salt thereof and the hyaluronidase are administered intermittently at a time interval of about three months to about two years” (claim 76) and “wherein the time interval is about three months to about six months” (claim 78), these limitations pertain to an intended use of the preparation and do not further limit the structure of the claimed product. Likewise, the newly added limitation “wherein a prolonged, extended, sustained release of rilpivirine or a pharmaceutically acceptable salt thereof into the blood plasma is maintained” is also an intended use and does not further limit the structure of the claimed product.
Regarding claim 81, treatment of HIV-1 is an intended use of the product that does not further limit the structure of the claimed product.
Regarding claim 82, claim 3 of ‘037 recites “rilpivirine or a pharmaceutically acceptable salt thereof.” Therefore, in one embodiment rilpivirine is not a salt.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 77 and 92 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3 and 15 of copending Application No. 18/858,037 (‘037), as applied to claims 76, 78, and 81-82 above, in view of Bookbinder.
See above for the recitation of claims 3 and 15 of ‘037, which is incorporated into this rejection as well.
Bookbinder claim 1 recites “a hyaluronidase glycoprotein that consists of the sequence of amino acids set forth as amino acids 1-477, 36-477, 1-478, 36-478, 1-479, 36-479, 1-480, 36-480, 1-481, 36-481, 1-482, 36-482, 1-483 or 36-483 of SEQ ID NO: 1,” wherein SEQ ID NO: 1 is 100% identical to the instant SEQ ID NO: 1 from residues 36 to 478 (OA Appendix A). Thus, Bookbinder teaches C- and N-terminal truncations of PH20 that include the instant SEQ ID NO: 1. Bookbinder also teaches that the 36-478 fragment of recombinant human hyaluronidase (rHuPH20) is both soluble and active (Bookbinder claim 7). Bookbinder teaches that C-terminal truncations of PH20 are secreted proteins (lines 18-20 of column 26). Bookbinder’s SEQ ID NO: 1 is recombinant human hyaluronidase PH20 (lines 59-62 of column 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use any one of the N- and C-terminal truncations of PH20 taught by Bookbinder in the reconstituted composition of claim 3o ‘037. The person of ordinary skill in the art would have been motivated by Bookbinder’s teaching that these fragments, including amino acid residues 36-478 of SEQ ID NO: 1, retain catalytic activity while having improved solubility (Bookbinder claim 7 and liens 18-20 of column 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 79-80 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3 and 15 of copending Application No. 18/858,037 (‘037), as applied to claims 76, 78, and 81-82 above, in view of Baert and as evidenced by Elan’s NanoCrystals.
See above recitation of claims 3 and 15 of ‘037, which is incorporated into this rejection as well.
Claims 3 and 15 of ‘037 do not recite that the nanoparticles have poloxamer adsorbed to their surface (instant claim 79) or that the average effective particle size of
the micro- or nanoparticles is less than about 1 micron (instant claim 80).
Baert teaches rilpivirine nanoparticles formulated as nanocrystals with poloxamer 338 as a surfactant (Abstract, page 503, left column “2.1. Test compounds and formulations” paragraph 2). The drug (rilpivirine) is thinly coated with the surface modifier poloxamer 338 (i.e. adsorbed) to impart physical stability, as evidenced by Elan’s NanoCrystals™ (page 2, first paragraph after second image).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to apply Baert’s technique to formulate the nanoparticles in the reconstituted composition of claim 3 of ‘037 and the person of ordinary skill in the art would have had a reasonable expectation of success given that Baert’s nanoparticles also comprise rilpivirine.
Regarding instant claim 80, Baert teaches that the particle size of the nanoparticles is less than 1 micron (200 nm, 400 nm, and 800 nm; see Abstract), but Baert does not teach the average effective particle size. Baert’s particle size is the mean volume diameter of the particles (page 503, right column, 2.2. Particle size determination and stability testing, paragraph 1).
However, since Baert is capable of producing three discrete particle sizes, all less than 1 micron, it would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the particle size distribution of the nanoparticles. The person of ordinary skill in the art would have had a reasonable expectation of success given that Baert already tests the production of three different sizes, each of which is less than 1 micron.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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 CANDICE LEE SWIFT whose telephone number is (571)272-0177. The examiner can normally be reached M-F 8:00 AM-4:30 PM (Eastern).
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657