DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . 1
Status of the Claims
Claims 15-16, 20, 30-32, 34-35, 37-43 and 45 are pending.
Terminal Disclaimer
The terminal disclaimer filed on March 18 2026 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of US Pat 12337063 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Response to Arguments
Applicant's amendments, cancelling of claims 18, 33 and 44, and arguments dated March 18 2026 with regard to the rejections of claims 15-16, 20, 30-35 and 37-44 as being obvious over Rajpal et al. in view of Rawas-Qalaji et al., as evidenced by Nibha and Pacholi have been fully considered. The rejection of Claims 15-16, 20, 30-35 and 37-44 has been withdrawn, and resulted in the below new rejections detailed below.
Note, a copy of the updated USP Friability Hardness test (updated Nov. 2016) has been entered into the record via PTO-892 form as relevant background art.
New Claim Rejections necessitated by amendment - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicants are advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 15-16, 20, 30-32, 34-35, 37-43 and 45 are rejected under 35 U.S.C. 103 as being unpatentable over Rajpal et al. American Journal of Emergency Medicine (2010) 28, 143–150 in view of Rawas-Qalaji et al. (AAPS PharmSciTech 2006; 7 (2) Article 41), as evidenced by Nibha and Pacholi “An Overview on: Sublingual Route for Systemic Drug Delivery,” Published April 2012. www.ijrpbsonline.com (Year: 2012).
The rejection’s references have been previously cited by the Examiner.
Claims 15, 32 and 39 have been discussed previously but now include limitations to recite administering to the subject the claimed atropine sulfate composition, amended to specify it as a sublingual table to recite a filler, superdisintegrant and lubricant, further specifying them as microcrystalline cellulose, hydroxypropyl cellulose and magnesium stearate, and in ranges of amounts per claim 39.
Regarding claims 15, 32 and 39, Rajpal discloses a novel atropine sulfate (AS) sublingual (SL) formulation (injection) to a subject in need of organophosphate poisoning (and therefore treating a symptom of such), 2 milligrams per 0.1 mL, a concentration that falls within that claimed, see abstract. Rajpal describes the advantages of SL administration in terms of better bioavailability, rapid onset of action and early atropinization, see abstract and Conclusions section, page 149.2 Rajpal teaches SL administration is a safe and efficacious procedure as an alternative to conventional IM injection, particularly in case of a chemical terrorism scenario where hundreds of victims may require immediate atropinization simultaneously, see abstract.
Rajpal teaches presently, there is no strategy in place for mass casualty at the field level because the intravenous or intramuscular routes are either not practical or may be very slow in eliciting the therapeutic response in field conditions (page 144 columns 1-2). Thus, Rajpal’s solution of the SL route will address this need.
Although teaching the limitations of treating organophosphate poisoning (OP) sublingually with atropine sulfate as claimed, Rajpal does not teach
1) a sublingual tablet (filler, superdisintegrant and lubricant),
2) does not explicitly recite the claimed concentration range of 1-20 % w/w and
3) does not explicitly recite the limitation of the tablet dissolving in under a minute.
With regard to bullet point 1), sublingual tablets are known in the art to achieve rapid dosing while avoiding first pass metabolism drugs (allowing rapid entry into the blood stream as opposed intramuscular or oral routes) as evidenced by Nibha 20123.
For example, Rawas-Qalaji teaches a sublingual (SL) formulation comprising a filler (microcrystalline cellulose), a superdisintegrant (hydroxypropyl cellulose), and lubricant (magnesium stearate) with an active ingredient (epinephrine) in concentrations (6 and 12%) that falls within the claimed percentage range of claim 32, see Table 1 of Rawas-Qalaji, page E2, reproduced below.
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Rawas-Qalaji teaches its tablets were designed to be a fast-disintegrating sublingual “tablets that disintegrate or dissolve rapidly in the patient's mouth,” see page E1 column 1 bridging to column 2. (emphasis added);4 for the treatment of an emergent situation (anaphylactic shock) that requires immediate release of a drug to a subject, (similar to the situation of organophosphate poisoning), see abstract.
With regard to bullet point 2) Rawas-Qalaji teaches its sublingual tablet formulation of Table 1 identified above comprises an active ingredient (epinephrine) in concentrations (6 and 12%) that falls within the claimed percentage range of claim 32, see Table 1 of Rawas-Qalaji, page E2, above.
Regarding bullet point 3), Rawas-Qalaji discloses in Figure 2 how its formulations of fast disintegrating tablets demonstrate they disintegrate in under a minute, (4 tablets dissolved in in less than 32.5 seconds). See Figure 2, page E5, column 1 top of column.
Prior to the filing of the present patent application, it would have been prima facie obvious to a person having ordinary skill in the art (PHOSITA) following the teachings of Rajpal to formulate atropine sulfate administered sublingually as a sublingual (SL) tablet based on the teachings of by Rawas-Qalaji (SL tablets comprising filler, superdisintegrant and lubricant to dissolve in under a minute) and evidenced by Nibha as the prior art recognizes the need for rapid administration of drugs (including atropine sulfate) sublingually (e.g. MPEP 2143 (a)).5
Initially, similar to Rawas-Qalaji, Rajpal discloses the benefits of sublingual route similar to those of Rawas-Qalaji. Therefore, a person having ordinary skill in the art (PHOSITA) would have a reasonable expectation of success in combining the cited references to arrive at the claimed invention because of the equivalency between the two routes of sublingual administration to rapidly deliver medications to the systemic circulation and avoid hepatic first pass metabolism. It is noted that further advantages of dosing via a rapidly dissolving sublingual tablet as per Rajpal (over the liquid sublingual administration of Rajpal) where Nibha 2012 discloses sublingual tablets advantages include ease of administration; convenience in administration of drug and accurate dosing as compared to liquid formulations; good mouth feel vs bitter pills; fast dissolution of medicament and absorption for rapid, onset of action; provides advantages of liquid formulations in the form of solid dosage form, see page 6, column 1, Section Advantages.
Further, a PHOSITA would have a reasonable expectation of success in arriving at the claimed invention because: 1) sublingual tablets are known in the art to achieve rapid dosing while avoiding first pass metabolism drugs (allowing rapid entry into the blood stream as opposed intramuscular or oral routes) as evidenced by Nibha 20126; 2) known doses of atropine sulfate per Rajpal (2 to 4 mg of atropine sulphate for unit doses, see page 144, first column last paragraph), would be routinely formulated into SL tablets of 150 mg total weight, that falls within the claimed 1-20% concentration) and 3) the limitation of disintegration of occurring in less than a minute in the oral cavity of the subject where sublingual are known to be dissolved in less than a minute as taught by Rawas-Qalaji.
Further, because the art teaches applicant’s claimed rapid release formulation, such disintegration in under one minute limitation is deemed to be necessarily present in the clamed invention.
As required by claims 32 and 39, Table 1 (reproduced above) of Rawas-Qalaji recites three specific excipients, microcrystalline cellulose (filler), hydroxypropyl cellulose (superdisintegrant), and magnesium stearate (lubricant).
Note that claim 39 is similarly directed to a method of treating symptoms of OP exposure with an atropine sulfate SL rapid disintegrating tablet, and specifies specific limitations regarding atropine sulfate, microcrystalline cellulose, hydroxypropyl cellulose and magnesium stearate, where overlapping ranges of excipients are taught by Table 1 as claimed by claim 39. As discussed above, the teachings of Rajpal, Rawas-Qalaji as evidenced by Nibha teach the limitations of claims 15 and 32, and render obvious claim 39.
Regarding claims 16 and 34, Rajpal discloses the increased use of OP pesticides and terror groups using nerve agents underscores the need to develop safe and effective antidotes, i.e. atropine sulfate, to treat the symptoms of OP exposure, see abstract.
Regarding claims 20, 37 and 41-42, Rajpal teaches the co-administration of the cholinesterase re-activator, pralidoxime chloride, see page 144, first column, first full paragraph.
Regarding claims 30 and 35, Rajpal teaches that SLUDGE (salivation (and its obvious variant hypersalivation), lacrimation, urination, diaphoresis, gastrointestinal motility, emesis) symptoms are caused by organophosphate poisoning, see page 144, first column first paragraph.
Regarding claim 31, Rawas-Qalaji teaches the same formulation of rapidly disintegrating/ buccal/sublingual tablet with the same excipients as claimed. Therefore,
while Rawas-Qalaji does not expressly recite the limitation of claim 31 of disintegration under a minute, because Rajpal and Rawas-Qalaji teaches applicant’s claimed rapid release formulation, (and without any further defining structure limitations amounts of excipients and active for example to distinguish from the cited prior art), such rapid, full disintegration and complete release properties are deemed to be necessarily present in the claimed invention.
Regarding claims 38 and 40, these range limitations (for MCC, hydroxypropyl cellulose and magnesium stearate)7 are disclosed by overlapping ranges by Table 1 of Rawas-Qalaji, see page E2.
Regarding claims 43 and 45, and the treatment of the symptoms, Rajpal teaches that SLUDGE (salivation, lacrimation, urination, diaphoresis, gastrointestinal motility, emesis) symptoms are caused by organophosphate poisoning, see page 144, first column first paragraph.
RESPONSE TO ATTORNEY ARGUMENTS;
The Attorney response argues the combination of cited art does not teach the invention, where there is not a sufficient rationale to show a PHOSITA would have had a reasonable expectation of success at the time of the filing to arrive at the claimed invention.
The Attorney response states the claims require that "rapid disintegration" is full disintegration of the sublingual tablet occurring in less than about a minute in the oral cavity, where claim 32 requires a composition including from about 1 to about 20 w/w% of atropine sulfate, microcrystalline cellulose, hydroxypropyl cellulose, and magnesium stearate, and claim 39 includes specific ranges of the excipients. The Attorney response states Rajpal does not teach or suggested all claimed limitations (because Rajpal’s sublingual context is with an injection, not the challenges of a 1-20% concentration atropine sulfate SL tablet) and neither Rawas-Qalaji and/or Nibha cure these deficiencies.
In response, while Rajpal teaches an alternative solution of a sublingual injection to a sublingual tablet, the mere teaching of alternative does not equate to a teaching away. “[T]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). Rajpal’s teaching of an alternative sublingual route does not necessarily teach away from other alternative sublingual routes such as tablets, absent an explicit critique, discrediting or otherwise discouraging of the solution (sublingual tablets) claimed.
The Attorney response states Rawas-Qalaji does not cure the deficiencies of Rajpal as Rawas-Qalaji refers to fast-disintegrating sublingual tablets of epinephrine, showing how excipient proportions and compression force influence hardness, wetting time, and disintegration time. The Attorney response states epinephrine is a small, relatively lipophilic molecule that can easily cross the oral mucosal barrier, while in contrast, atropine sulfate is a hydrophilic salt form of a significantly larger molecule (referencing Takagi et al. and Zhang, Exhibits A and B). The Attorney response states the discussion of Nibha is high-level and does not teach how to formulate atropine sulfate into a fast-disintegrating tablet that not only achieves the claimed disintegration time but also provides sufficient sublingual absorption to treat symptoms of organophosphate toxicity; generalized advantages of the sublingual route are not a blueprint for overcoming the molecule-specific permeability challenges presented by atropine sulfate.
As detailed in the previous response, the Examiner notes that the physical characteristics of molecular weight and lipophilicity (from Nibha and Exhibits A and B) are to be taken in context as general guidance and not absolutes to prevent the formulation of atropine sulphate into sublingual tablets, for Example from Nibha. The laundry list of drug compounds from Nibha is noted to reflect the diverse types of drug compounds in terms activity and physical properties that can be formulated into sublingual formulations. Despite the Attorney’s response that certain generalized guidelines from Nibha are rigidly applied to exclude a rationale to use atropine sulfate in sublingual formulations, Nibha notes many different drugs with differing physical properties can be used with SL formulations.
Nibha does provide the advantages of sublingual tablets in general, and discusses high MW drugs as suitable for sublingual administration. See above advantages of SL tablets taught by Nibha as summarized at page 6, column 1, Section Advantages.8
The Attorney response states because the claims require a sublingual tablet about 1 to about 20 wt% atropine sulfate, a filler, a superdisintegrant, and a lubricant, the cited prior art does not teach or suggest administering such a sublingual tablet for rapid disintegration and absorption into systemic circulation of the subject.
The Attorney response states it is only through hindsight that 2 to 4 mg atropine sulfate is formulated into SL tablets of 150 mg of total weight to treat the symptoms of organophosphate toxicity as claimed.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As detailed above, the combination of prior art notes that per known doses of atropine sulfate per Rajpal (2 to 4 mg of atropine sulphate for unit doses, see page 144, first column last paragraph), would be routinely formulated into SL tablets of 150 mg total weight, as per Rawas-Qalaji Table 1, where the amount of active in a tablet of 150 mg total weight, overlaps with a claimed 1-20% concentration of active ingredient.
The Attorney response states because Takagi teaches the large molecular properties of atropine sulfate with low permeability, they would have no reasonable expectation of success to achieve the treatment of at least one symptom of such OP exposure.
In response, as detailed above, the combination of cited prior art teaches the claimed method, where it would be obvious to teach such symptoms as detailed above.
The Attorney response revisits there is no expectation of success by noting atropine sulfate differs from epinephrine because its low permeability (citing to Takagi and citing to Nibha, that particle size/physico-chemical nature of a formulation effect the flux of a compound). The Attorney response states none of the cited art teaches atropine sulfate sublingual delivery requires rapid disintegration and sufficient transmucosal flux to achieve therapeutic plasma levels quickly, via rapidly disintegrating tablets with systemic circulation absorption. The Attorney response states individually Rajpal does not teach SL tablets of atropine sulfate, Rawas-Qalaji only teaches MCC, hydroxypropyl cellulose and Mg stearate in epinephrine tablets without regard to atropine sulfate’s challenges of rapid disintegration and absorption into systemic circulation, etc.
While the Attorney response states the combination of art does not provide a reasonable expectation of success to teach or suggest the invention, it is noted that the response notes individual deficiencies of each of Rajpal, Rawas-Qalaji and Nibha to support its arguments, while also referencing its submitted Exhibits A and B. As detailed in the rejection, the combination of cited prior art spells out the rejection of the claimed invention.9
The Attorney response summarizes its invention addresses a long recognized need for a field-deployable dosage form (SL tablet) with rapid onset for OP poisoning, where minutes matter, avoids first pass hepatic metabolism and acidic GI tract; patient friendly, convenient and cost-effective, without the limitations of injections and parenteral administration.
The Attorney response cites to MPEP 2143, claim elements (rapidly disintegrating for systemic circulation absorption, less than 1 minute, SL composition about 1 to about 20% atropine sulfate) are missing from the prior art, as well as an absence of reasoned explanation to guide the PHOSITA to the invention without impermissible hindsight.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). As detailed above, the combination of prior art notes that per known doses of atropine sulfate per Rajpal (2 to 4 mg of atropine sulphate for unit doses, see page 144, first column last paragraph), would be routinely formulated into SL tablets of 150 mg total weight, as per Rawas-Qalaji Table 1, where the amount of active in a tablet of 150 mg total weight, overlaps with a claimed 1-20% concentration of active ingredient.
Experimental data under the requirements and standards of MPEP 716.02 to demonstrate unexpected results of the claimed method will overcome the prima facie case to result in an allowance.
Conclusion and Correspondence
In summary, no claims are 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 WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 This application is a 371 of PCT/US15/53713 10/02/2015. PCT/US15/53713 has priority to US Provisional 62/058,722 filed 10/02/2014. This application has published as US20170246158A1.
2 As detailed in the previous office action, Rajpal discloses SL route of administration is receiving attention because “it avoids the first pass of metabolism of the drug, allowing it to enter the blood stream earlier than intramuscular or oral route.” See page 148, Section 4 discussion, column 1. Rajpal discloses its results provide the first evidence of the clinical effects and blood levels of sublingual atropine, Id. Rajpal discloses “Enhanced absorption from the sublingual route is because of its high perfusion, and the venous drainage from glossal/sublingual region to the large central veins of neck may increase the transport of injected drug to the muscarinic receptors of heart.” Id. .
3 Nibha and Pacholi “An Overview on: Sublingual Route for Systemic Drug Delivery,” Published April 2012. www.ijrpbsonline.com, Footnote 9 citing to in, Richman MD, Fox D, Shangraw RF. Preparation and stability of glyceryl trinitrate sublingual tablets prepared by direct compression. J Pharm Sci 1965; 54(3): 447‐451.
4 Rawas-Qalaji further teaches advantages of its tablets are that they:
are convenient for young children, the elderly and patients with swallowing difficulties, and in situations where potable liquids are not available. For these formulations, the small volume of saliva is usually sufficient to result in tablet disintegration in the oral cavity. The medication can then be absorbed partially or entirely into the systemic circulation from blood vessels in the sublingual mucosa. . . . The sublingual route usually produces a faster onset of action than orally ingested tablets and the portion absorbed through the sublingual blood vessels bypasses the hepatic first-pass metabolic processes. See page E1, column 2. (emphasis added)
5 MPEP 2143 sets forth some rationales that were established in KSR Int'! Co. v Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007). Exemplary rationales that may support a conclusion of obviousness include:
(a) combining prior art elements according to known methods to yield predictable results;
6 Nibha and Pacholi “An Overview on: Sublingual Route for Systemic Drug Delivery,” Published April 2012. www.ijrpbsonline.com, Footnote 9 citing to in, Richman MD, Fox D, Shangraw RF. Preparation and stability of glyceryl trinitrate sublingual tablets prepared by direct compression. J Pharm Sci 1965; 54(3): 447‐451.
7 The claim 39 limitations are wherein the composition comprises from about 20 to about 95 wt% of microcrystalline cellulose as the filler, from about 1 to about 15 wt% of hydroxypropyl cellulose as the super disintegrant, and from about 0.5 to about 3 wt% of magnesium stearate as the lubricant.
The claim 40 limitations are wherein the pharmaceutical composition comprises 1 to 16 wt% of atropine sulfate, 70 to 90 wt% of microcrystalline cellulose, 8 to 10 wt% of hydroxypropyl cellulose, and 0.5 to 2 wt% of magnesium stearate.
8 As recited in the obviousness rejection, Nibha 2012 discloses sublingual tablets advantages include ease of administration; convenience in administration of drug and accurate dosing as compared to liquid formulations; good mouth feel vs bitter pills; fast dissolution of medicament and absorption for rapid, onset of action; provides advantages of liquid formulations in the form of solid dosage form, see page 6, column 1, Section Advantages.
9 See MPEP 2145 IV. Per MPEP 707.07(f), Form Paragraph 07-37-13. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
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