COMPOSITIONS AND METHODS FOR DELIVERING PHARMACEUTICAL AGENTS

DETAILED ACTION Applicants’ arguments, filed 9 September 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application. Claim Interpretation Claim 1 has been amended to require that the composition is formulated for oral, intravenous, intraperitoneal, or subcutaneous administration. The examiner presents the following explanation regarding how this limitation will be interpreted for the purposes of examination under prior art. The examiner notes that apparatus claims cover what a device is, not what a device does. As such, a claim containing a recitation with respect to the manner in which a claimed apparatus is intended to be employed does not differentiate the claimed apparatus from a prior art apparatus if the prior art apparatus teaches all the structural limitations of the claim. See MPEP 2114(II). The examiner understands the rationale in MPEP 2114(II) to apply to chemical composition claims in the manner that it applies to apparatus claims. Therefore, for the purposes of examination under prior art, the examiner understands that a composition that could have been administered orally, intravenously, intraperitoneally, or subcutaneously to have meet the requirements of the last two lines of claim 1 even if the prior art does not teach this mode of administration. See also MPEP 2111.02(II), 2112(I & II), 2112.01(I & II), and 2144(IV), which are also relevant to this matter. Note Regarding Formoterol The instant claims have been limited to a dosage form comprising formoterol. The skilled artisan would have recognized, prior to the effective filing date of the instant application, that a common side effect of formoterol is increased heart rate and decreased diastolic blood pressure, especially in the few minutes after administration. See e.g. Guhan et al. (Thorax, Vol. 55, 2000, pages 650-656). Guhan et al. (hereafter referred to as Guhan) teaches the following, as of Guhan, page 653, relevant text reproduced below. PNG media_image1.png 166 418 media_image1.png Greyscale PNG media_image2.png 324 424 media_image2.png Greyscale The examiner notes that in Guhan, the formoterol is being administered via inhalation, which appears to be a different route of administration than what is intended by the instant application. Nevertheless, there would have been a reasonable expectation that these side effects would have occurred regardless of the route of administration. Claim Rejections - 35 USC § 112(b) – Indefiniteness The following is a quotation of 35 U.S.C. 112(b): (b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention. The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph: The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention. Claims 1-2, 4, 6-12, and 14-15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. Claim 1 recites the phrase “methyl ether-block-poly(lactide-co-glycolide) (PLGA)” as of the third and fourth line of claim 1. It is unclear how the term “block” further limits the claimed polymer. The examiner notes that the term “block” is frequently used in polymer science to refer to a block copolymer. This is a copolymer that comprises at least two polymer blocks, wherein each polymer block is made from the polymerization of particular monomers. A block copolymer differs from a random copolymer in that a block copolymer comprises a unit made entirely of the polymer formed by the polymerization of the first monomer separate from a unit made entirely of the polymer formed by the polymerization of the second monomer. As such, if e.g. the first monomer is hydrophobic and the second monomer is hydrophilic, this leads to a polymer with a hydrophobic region and a separate hydrophilic region, which would not occur with a random copolymer. See e.g. Oda et al. (Biomacromolecules, Vol. 12, 2011, pages 3581-3591), which explains block copolymers and compares them to random copolymers, as of at least page 3582, left column, figure 1, reproduced below. PNG media_image3.png 413 600 media_image3.png Greyscale With that being said, in this case, “methyl ether” is not a polymer; as such, a methyl ether polymer block cannot form. As such, it is unclear how the phrase “block” further limits the claim requirements drawn to a methyl ether block of a certain polymer given that methyl ether, not being a polymer, cannot form a polymer block. This rationale occurs to the occurrence of the term “methyl ether-block” in the third and fourth lines of claim 1. In regard to claim 1, lines 7-10, the examiner additionally notes that since PLGA comprises ester groups, an end modification of PLGA with a methyl group would likely have formed a methyl ester rather than a methyl ether. For the purposes of examination under prior art, the examiner will examine the claims with the understanding that the phrase “methyl ether-block” in the third and fourth lines of claim 1 as well as the seventh through tenth lines of claim 1 does not further limit the claim. With that being said, the examiner clarifies that the limitation “poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide)” in the 5th and 6th lines of claim 1 appears to be definite. This is because in this case, there is a block copolymer with a poly(ethylene glycol) block and a poly(lactide-co-glycolide) block. The term “methyl ether” in this case limits the terminus of the poly(ethylene glycol) block, but is not a block of the polymer itself, and is therefore definite and understood to further limit the claim. Response to Arguments Regarding Indefiniteness Issue In applicant’s response on 9 September 2026 (hereafter referred to as applicant’s response), applicant argues that the claim amendments overcome the applied rejection under 35 U.S.C. 112(b), as of applicant’s response on 9 September 2026, page 6. The examiner disagrees. This is at least because claim 1, line 5 still recites “methyl ether block poly(lactide-co-glycolide). Additionally, the claims still recite that the PLGA has a methyl ether endgroup rather than a methyl ester endgroup. Claim Rejections - 35 USC § 112(a) – New Matter The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claims 1-2, 4, 6-12, and 14-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. Instant claim 1 has been amended to recite the following limitation. PNG media_image4.png 132 572 media_image4.png Greyscale This newly added limitation does not appear to be adequately described by the original application as filed and therefore appears to be new matter. The examiner presents the following rationale in support of this position. In applicant’s response on 9 September 2026 (hereafter referred to as applicant’s response), applicant cited figure 7 and the accompanying description as allegedly supporting the claim amendment. Figure 7 has been reproduced below. PNG media_image5.png 358 632 media_image5.png Greyscale The instant specification describes figure 7 on page 5, bottom paragraph. This paragraph is reproduced below. PNG media_image6.png 210 622 media_image6.png Greyscale As such, the description clarifies that the data from figure 7 was taken on C57BL/6 mice. In order to better understand the above-reproduced data, the examiner conducted a search in order to determine what is the “normal” heart rate, mean arterial pressure, and diastolic blood pressure in C57BL/6 mice. In view of such a search, the examiner cites Mattson (American Journal of Hypertension, Vol. 14, No. 5 Part 1, May 2001, pages 405-408). Mattson teaches the following on page 407, relevant text reproduced below with the relevant type of mouse pointed out by the examiner. PNG media_image7.png 380 1308 media_image7.png Greyscale The above-reproduced data appears to disclose the mean arterial pressure, diastolic blood pressure, and heart rate in the C57BL/6J mouse, which appears to be within the genus of the C57BL/6 mouse disclosed in the instant specification. The inquiry into whether the description requirement is met must be determined on a case-by-case basis and is a question of fact. A description as filed is presumed to be adequate, unless or until sufficient evidence or reasoning to the contrary has been presented by the examiner to rebut the presumption. The examiner, therefore, must have a reasonable basis to challenge the adequacy of the written description. See MPEP 2163.04. The examiner takes the position that the Mattson reference provides sufficient evidence to rebut the presumption of adequacy of the disclosure of figure 7 of the instant application for at least the following reasons. Heart Rate: Mattson indicates that the normal heart rate in a C57BL/6 mouse is about 594 beats per minute. In contrast, figure 7 measured closer to 300 beats per minute in mice not treated with formoterol, as of the first column of the left-most graph of figure 7 labeled “Vehicle Control.” That the normal heart rate of untreated mice was half as fast as what was measured by Mattson calls into question the accuracy of the data related to heart rate. Diastolic Blood Pressure: Figure 7, right-most graph, measures diastolic blood pressure. The examiner clarifies that blood pressure, e.g. when measured at the doctor’s office, is measured with two numbers. The first number is higher and is the systolic blood pressure. The second number is lower and is the diastolic blood pressure. Mattson indicates that the normal diastolic blood pressure in C57BL/6J mice is about 99 mmHg. For reference, this is only about 19 mmHg higher than the normal diastolic blood pressure of 80 mmHg in humans – as best understood by the examiner, the blood pressure most preferred by doctors for adult humans is 120 bpm systolic blood pressure and 80 bpm diastolic blood pressure. Figure 7 shows a diastolic blood pressure of about 118 mmHg in untreated mice, which is almost 20 mmHg above the normal diastolic blood pressure taught by Mattson. This would appear to indicate that the mice taught by Mattson as normal were actually suffering from hypertension, thereby calling into question the accuracy of the data with respect to diastolic blood pressure. Ironically, the mice treated with formoterol in the absence of the delivery nanoparticle appear to have a diastolic blood pressure close to normal (for the disclosed mouse strain), indicating that formoterol is actually being used as an anti-hypertension agent rather than a drug that has a dangerous side effect of potentially causing a hypotensive emergency. Mean Arterial Pressure: As explained above, blood pressure is measured by measuring systolic blood pressure and diastolic blood pressure. The mean arterial pressure would appear to be the average of systolic and diastolic blood pressure. However, figure 7 would appear to show a mean arterial pressure of about 121 mmHg, which is only slightly higher than the diastolic blood of about 118 mmHg. This small difference between diastolic blood pressure and mean arterial pressure is much smaller than what is taught by Mattson, which indicates an 11 mmHg difference between diastolic blood pressure and mean arterial pressure. This calls into question the accuracy of the data with respect to mean arterial pressure. In view of the significant differences between the “vehicle control” of figure 7 and the average heart rate and blood pressure for C57BL/6 mice measured by Mattson, the examiner has sufficient reason to doubt the accuracy of the disclosure of figure 7 of the instant specification. This results in a prima facie case of lack of adequate written description. Claim Rejections - 35 USC § 112(a) – Scope of Enablement The following is a quotation of the first paragraph of 35 U.S.C. 112(a): (a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention. The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112: The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention. Claims 1-2, 4, 6-12, and 14-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a pharmaceutical composition comprising formoterol and a block copolymer, does not reasonably provide enablement for a composition which does not result in a significant increase in heart rate or a significant decrease in mean arterial pressure or diastolic blood pressure within 1 to 2 hours of administration, relative to administration of an equivalent dose of formoterol in free form. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims. In order to make a rejection for lack of enablement, the examiner has the initial burden to establish a reasonable basis to question the enablement provided for the claimed invention; as such, the examiner must provide a reasonable explanation as to why the scope of protection provided by a claim is not adequately enabled by the disclosure. A specification disclosure, including the drawings, which contains a teaching of the manner and process of making and using an invention in terms which correspond in scope to those used in describing and defining the subject matter sought to be patented must be taken as being in compliance with the enablement requirement of 35 U.S.C. 112(a) unless there is a reason to doubt the objective truth of the statements contained therein which must be relied on for enabling support. See MPEP 2164.04. Assuming that sufficient reason for such doubt exists, a rejection for failure to teach how to make and/or use will be proper on that basis. As such, it is incumbent upon the Patent Office, whenever a rejection on this basis is made, to explain why it doubts the truth or accuracy of any statement in a supporting disclosure and to back up assertions of its own with acceptable evidence or reasoning which is inconsistent with the contested statement. See MPEP 2164.04, second paragraph. In applicant’s most recent response, applicant amended claim 1 to recite the following: PNG media_image4.png 132 572 media_image4.png Greyscale This newly added limitation does not appear to be properly enabled because there is a reason to doubt the statements in the specification drawn to this matter. The examiner presents the following rationale in support of this position. In applicant’s response on 9 September 2026 (hereafter referred to as applicant’s response), applicant cited figure 7 and the accompanying description as allegedly supporting the claim amendment. Figure 7 has been reproduced below. PNG media_image5.png 358 632 media_image5.png Greyscale The instant specification describes figure 7 on page 5, bottom paragraph. This paragraph is reproduced below. PNG media_image6.png 210 622 media_image6.png Greyscale As such, the description clarifies that the data from figure 7 was taken on C57BL/6 mice. In order to better understand the above-reproduced data, the examiner conducted a search in order to determine what is the “normal” heart rate, mean arterial pressure, and diastolic blood pressure in C57BL/6 mice. In view of such a search, the examiner cites Mattson (American Journal of Hypertension, Vol. 14, No. 5 Part 1, May 2001, pages 405-408). Mattson teaches the following on page 407, relevant text reproduced below with the relevant type of mouse pointed out by the examiner. PNG media_image7.png 380 1308 media_image7.png Greyscale The above-reproduced data appears to disclose the mean arterial pressure, diastolic blood pressure, and heart rate in the C57BL/6J mouse, which appears to be within the genus of the c57BL/6 mouse disclosed in the instant specification. The examiner takes the position that the Mattson reference provides sufficient evidence to doubt the objective truth of the statements in figure 7 of the instant application and of portions of the specification relating to figure 7, wherein reasons for such doubt would render proper a rejection for failure to teach how to make and/or use the claimed invention. See MPEP 2164.04, second paragraph. The examiner presents the following rationale below explaining why the teachings of Mattson result in a reason to doubt the objective truth of the statements in figure 7 of the instant application. Heart Rate: Mattson indicates that the normal heart rate in a C57BL/6 mouse is about 594 beats per minute. In contrast, figure 7 measured closer to 300 beats per minute in mice not treated with formoterol, as of the first column of the left-most graph of figure 7 labeled “Vehicle Control.” That the normal heart rate of untreated mice was half as fast as what was measured by Mattson calls into question the accuracy of the data related to heart rate disclosed in figure 7. Diastolic Blood Pressure: Figure 7, right-most graph, measures diastolic blood pressure. The examiner clarifies that blood pressure, e.g. when measured at the doctor’s office, is measured with two numbers. The first number is higher and is the systolic blood pressure. The second number is lower and is the diastolic blood pressure. Mattson indicates that the normal diastolic blood pressure in C57BL/6J mice is about 99 mmHg. For reference, this is only about 19 mmHg higher than the normal diastolic blood pressure of 80 mmHg in humans. Figure 7 shows a diastolic blood pressure of about 118 mmHg in untreated mice, which is almost 20 mmHg above the normal diastolic blood pressure taught by Mattson – as best understood by the examiner, the blood pressure most preferred by doctors for adult humans is 120 bpm systolic blood pressure and 80 bpm diastolic blood pressure. This would appear to indicate that the mice taught by Mattson as normal were actually suffering from hypertension, thereby calling into question the accuracy of the data with respect to diastolic blood pressure. Ironically, the mice treated with formoterol in the absence of the delivery nanoparticle appear to have a diastolic blood pressure close to normal, indicating that formoterol is actually being used as an anti-hypertension agent rather than a drug that has a dangerous side effect of potentially causing a hypotensive emergency. Mean Arterial Pressure: As explained above, blood pressure is measured by measuring systolic blood pressure and diastolic blood pressure. The mean arterial pressure would appear to be the average of systolic and diastolic blood pressure. However, figure 7 would appear to show a mean arterial pressure of about 121 mmHg, which is only slightly higher than the diastolic blood of about 118 mmHg. This small difference between diastolic blood pressure and mean arterial pressure is much smaller than what is taught by Mattson, which indicates an 11 mmHg difference between diastolic blood pressure and mean arterial pressure. This calls into question the accuracy of the data with respect to mean arterial pressure. In view of the significant differences between the “vehicle control” of figure 7 and the average heart rate and blood pressure for C57BL/6 mice measured by Mattson, the examiner has sufficient reason to doubt the disclosure of figure 7 of the instant specification. As figure 7 of the instant specification is drawn to the claim limitation recited on the last four lines of claim 1, the examiner takes the position that the claim limitation recited on the last four lines of claim 1 is not enabled in view of the provisions of MPEP 2164.04, second paragraph. Withdrawn Prior Art Rejections The instant claims were previously rejected as obvious over the combination of Beck-Broichsitter et al. (Journal of Aerosol Medicine and Pulmonary Drug Delivery, Vol. 23, No. 1, 2010, pages 47-57) in view of Varshosaz et al. (Research in Pharmaceutical Sciences, 12(3), June 2017, pages 222-232). The instant claims were also previously rejected as obvious over the combination of Heller et al. (US 2018/0243227 A1) in view of Schnellmann et al. (US 2014/0024677 A1). Both rejections have been withdrawn. The examiner presents the following rationale for withdrawing these rejections. Broichsitter in view of Varshosaz Rejection Withdrawn: Beck-Broichsitter et al. (hereafter referred to as Broichsitter) is drawn to biodegradable salbutamol-loaded nanoparticles, as of Broichsitter, page 47, title and abstract. The biodegradable nanoparticles of Broichsitter may comprise PLGA. Varshosaz et al. (hereafter referred to as Varshosaz) is drawn to PLGA loaded nanoparticles comprising tadalafil, as of Varshosaz, page 222, title and abstract. Neither reference teaches formoterol. Furthermore, neither reference teaches that administration of the composition does not result in a significant increase in heart rater or a significant decrease in mean arterial pressure or diastolic blood pressure within 1 to 2 hours, relative to administraiton of an equivalent dose of formoterol in free form. As such, the previously applied rejection of Broichsitter in view of Varshosaz has been withdrawn. Heller in view of Schnellmann Rejection Withdrawn: Heller et al. (hereafter referred to as Heller) is drawn to a drug nanoparticle for targeting the proximal tubules of the kidneys, as of Heller, title and abstract. The drug nanoparticle of Heller may be made from PLGA-mPEG, as of Heller, paragraph 0176. Heller teaches PLGA-PEG-COOH in paragraph 0164 Heller does not teach a β-adrenergic agent. Schnellmann et al. (hereafter referred to as Schnellmann) is drawn to the treatment of acute kidney disease, as of Schnellmann, title and abstract. Schnellmann teaches formoterol for this purpose, as of the abstract, as well as paragraphs 0142-0143. There would have been no evidence that Heller by itself, Schnellmann by itself, or the combination of Heller in view of Schnellmann would have successfully resulted ina composition that when administered, does not result in a significant increase in heart rate or a significant decrease in mear arterial pressure or diastolic blood pressure within 1 to 2 hours of administration relative to an equivalent dose of formoterol in free form. The fact that a certain result or characteristic (e.g. the above indicated heart rate or blood pressure) may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic. See MPEP 2112(IV). Additionally, the skilled artisan would not have known how to have optimized the prior art to have achieved this property. Obviousness based upon routine optimization requires a reasonable expectation of success. See MPEP 2144.05(II)(B), first paragraph in section. In this case, there would have been no reasonable expectation that Heller and Schnellmann could have been optimized to have achieved this property. In view of the withdrawal of the previously applied prior art rejection, applicant’s arguments related to the previously presented prior art rejections are understood to be moot, and will therefore not be addressed substantively in this office action. Note Regarding Potential Claim Amendment and After-Final Consideration The examiner notes the following regarding a potential claim amendment. If applicant were to amend claim 1 to delete the phrase “wherein administration of said composition does not result in a significant increase in heart rate or a significant decrease in mean arterial pressure or diastolic blood pressure within 1 to 2 hours of administration, relative to administration of an equivalent dose in free form”, such an amendment would overcome the above-applied rejections under 35 U.S.C. 112(a). However, such an amendment would also require reconsideration of the examiner’s decision to withdrawn the prior art rejections, especially that over Heller in view of Schnellmann. As such, the above-indicated amendment would not be entered after-final in the absence of an RCE as it would necessitate further search and consideration. Conclusion No claim is allowed. 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 ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. 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If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000. ISAAC . SHOMER Primary Examiner Art Unit 1612 /ISAAC SHOMER/ Primary Examiner, Art Unit 1612