*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 .
Applicant's response dated June 12, 2026 is acknowledged.
Applicant submitted five non-patent literature documents in the response. It is noted that these references are not considered because applicant did not provide an information disclosure statement listing the references for consideration.
Priority
This application is a 371 of PCT/CN2021/126995 filed on 12/28/2021.
Claim Status
Claims 27, 29, 30, and 32-36 are pending and examined. Claims 1-26, 28, and 31 were canceled.
Withdrawn Claim Rejections - 35 USC§ 112
Rejections of claims 32, 33, and 35 are withdrawn because the claims were amended to obviate the grounds of rejection and applicant’s argument regarding low-substituted hydroxypropyl cellulose is persuasive in view of Yunes (ej EFSA Journal, Scientific Opinion, 2018; 16(1): 5062, pages 1-12).
New Claim Rejections - 35 USC§ 112
Necessitated by Amendment
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 29 and 30 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 29 and 30 are indefinite because the claims depend from a canceled claim 28. For the purpose of applying prior art, the claims are interpreted as dependents of claim 27. This is the broadest reasonable interpretation of the claims in view of the specification.
Maintained Claim Rejections - 35 USC § 103
Modified as Necessitated by Amendment
In the event the determination of the status of the application as subject to AIA 35 U.S.C.
102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the
statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a
new ground of rejection if the prior art relied upon, and the rationale supporting the rejection,
would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness
rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35
U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the
claims the examiner presumes that the subject matter of the various claims was commonly
owned as of the effective filing date of the claimed invention(s) absent any evidence to the
contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and
effective filing dates of each claim that was not commonly owned as of the effective filing date
of the later invention in order for the examiner to consider the applicability of 35 U.S.C.
102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 27 and 32-36 are rejected under 35 U.S.C. 103 as being unpatentable over
Bolen (US 2018/0193270 Al Published July 12, 2018 - of record in IDS dated 04/25/2024) and
Schwarz (US 2018/0311146 Al Published November 1, 2018).
The claims are drawn to a sublingual tablet, wherein the tablet includes drug-loaded milk
exosomes.
The teachings of Bolen are related to exosomes as drug delivery vehicles and
compositions comprising a therapeutic agent encapsulated within such exosomes (Abstract). In
some embodiments, exosome is a milk-derived exosome (paragraph 0064). In one aspect, a
therapeutic-loaded milk exosome is provided, wherein the therapeutic is a biologic therapeutic
agent and the therapeutic is not naturally-occurring in a milk exosome (paragraph 0076). In some
embodiments, the therapeutic-loaded exosomes or pharmaceutical compositions thereof are
administered by sublingual route (paragraphs 0074 and 0650). Table I teaches exemplary
therapeutic agents which include insulin and insulin detemir (paragraph 0601). Pharmaceutically
acceptable compositions may be orally administered in any orally acceptable dosage form
including, but not limited to tablets (paragraph 0653).
Bolen does not specifically teach tablets as a sublingual dosage from.
The teachings of Schwarz are related to self-emulsifying compositions for transmucosal
delivery of biologically active peptides and proteins (Abstract). The compositions are intraoral
solid pharmaceutical compositions for sublingual administration containing a biologically active
peptide such as insulin or insulin analogs, glucagon-like peptide and analogs such as GLP-1,
exenatide, or liraglutide (paragraph 0040). The composition for delivery of insulin and other
peptides may be in the form of a compressed tablet. Additionally, the tablet can comprise nonionic surfactants, fillers, such as pharmaceutical grade polyols or sugars (e.g., sucrose, sorbitol, mannitol, erythritol), binders (Polyvinylpyrrolidone, cellulose esters, polyethylene glycols), disintegrants (cross-carmellose, cross-povidone ), preservatives ( e.g., parabens, sorbic acid, benzoic acid and pharmaceutically acceptable salts thereof), lubricants, glidants, flavors,
antioxidants, etc. These components are incorporated into tablet matrix, prepared by granulation,
blending and compression (paragraph 0052). Tablet matrix granulate, containing insulin and
other excipients and suitable for compression, could be prepared by wet granulation, compaction,
trituration or dry blending. Tablets were compressed into round, oval or other required shape
tablets using appropriate tablet press (paragraph 0053).
The teachings of Bolen and Schwarz are related to peptide drugs such as insulin intended
for sublingual administration and it would have been obvious to have combined their teachings
because they are in the same field of endeavor.
Regarding claim 27, it would have been prima facie obvious to a person of ordinary skill
in the art before the effective filing date of the claimed invention to have formulated a
pharmaceutical composition comprising drug-loaded milk exosomes wherein the composition is
intended for sublingual administration, with a reasonable expectation of success because Bolen
teaches drug-loaded milk exosomes as drug carriers wherein the exosomes are formulated into a
pharmaceutical composition intended for sublingual administration. It would have been obvious
to have selected as peptide drug such as insulin as the active agent because Bolen teaches that
peptide drugs such as insulin are suitable for delivery via exosomes. While Bolen teaches
formulating oral dosage forms into a tablet, Bolen does not specifically teach a sublingual dosage
form in the form of a tablet. It would have been obvious to have formulated the sublingual
dosage form in the form of a sublingual tablet with a reasonable expectation of success because
Schwarz teaches that peptide drugs such as insulin may be administered sublingually via a
sublingual tablet. The selection of a known material based on its suitability for its intended
purpose supports obviousness and combining prior art elements according to known methods to
obtain predictable results supports obviousness.
It would have been obvious to have formulated the sublingual tablet with liraglutide as the active agent, with a reasonable expectation of success because Schwarz teaches that liraglutide is a suitable peptide drug that may be administered sublingually via a sublingual tablet. Alternatively, it would have been obvious to have formulated the tablet with insulin detemir, with a reasonable expectation of success because Bolen teaches that insulin
detemir is a suitable drug for sublingual administration.
Regarding claims 32 and 33, it would have been obvious to have formulated the tablet
with starch and mannitol because Schawrz teaches tablets in Table 4 that contain starch and
mannitol (paragraph 0173).
Regarding claim 34, it would have been obvious to have formulated the tablet with
sucralose because Schwarz teaches tablets in Tables 2 and 3 which contain sucralose (paragraph
0173).
Regarding claim 35, it would have been obvious to have formulated the tablet with
polyvinylpyrrolidone because Schwarz teaches tablets in Tables 2, 3, and 4 which contain
polyvinylpyrrolidone (paragraphs 0173).
Regarding claim 36, it would have been obvious to have formulated the tablet with
hydrogenated PEG-40 castor oil because Schwarz teaches tablets in Tables 2, 3, and 4 which
contain hydrogenated PEG-40 castor oil (paragraph 0173). Castor oil is a vegetable oil.
Alternatively, it would have been obvious to have formed the tablet with PEG 3350 because
Schwarz teaches tablets in Tables 2, 3, and 4 which contain PEG 3350. Polyethylene glycol 4000
is obvious over PEG 3350 because their molecular weights are close enough in number that the
skilled artisan would have expected them to have the same properties. PEG 4000 contains about
90 repeating units whereas PEG 3350 contains about 76 repeating units. Alternatively, it would have been obvious to have formulated the tablet with a lubricant because Schwarz teaches that the tablet contains lubricants (paragraph 0052). It would have been obvious to have selected magnesium stearate as the lubricant with a reasonable expectation of success because Bolen teaches magnesium stearate as a lubricant suitable for making an oral tablet (paragraph 0653).
Claim 29 are rejected under 35 U.S.C. 103 as being unpatentable over Bolen and
Schwarz as applied to claims 27 and 32-36 above, and further in view of Lee (2016/0375018
Al Published December 29, 2016).
The claim encompasses the sublingual tablet of claim 28 and further define the
excipients.
The teachings of Bolen and Schwarz are relied upon as summarized above. They do not
teach purified water in the tablet.
The teachings of Lee are related to solid drug formulations (Abstract). The dosage form
comprises diluents, disintegration agents, binding agents, wetting agents or lubricants. In one
embodiment, the diluents are lactose hydrate and microcrystalline cellulose; the disintegration
agents are cross-linked sodium carboxymethyl cellulose and sodium carboxymethyl starch; the
binding agents are hydroxypropyl cellulose and polyvinylpyrrolidone; and the lubricants are
magnesium stearate and stearic acid. See Table 2 for concentrations (paragraph 0025). The solid
drug formulations include dosage forms such as sublingual tablets. In one embodiment, the tablet
is formed by granulation and after the granulation step is accomplished, the wet clot is sieved
through a mesh with sieves to remove the agglomerates and increase the drying efficiency. The
fluidized bed dryer or the drying oven may be used for drying until the water content is 0.1-2%
wt. After drying achieves standard, the dried granules are sieved through a mesh with 30 sieves
to remove the agglomerates to forma first mixture. Next, the additional excipients such as
microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and magnesium stearate
are sieved through a mesh with 30 sieves to remove the agglomerates, and subsequently added
into the aforementioned completely dried granules (first mixture) and mix evenly to form a
second mixture. The mixed granules undergo powdered molding in an appropriate tablet mold
and tablet machine to form a solid dosage form. In one embodiment, the weight percentage of
polysorbate in the final solid dosage form (comprising added component after granulation) is
0.1-0.6% wt., for example, is 0.3% wt.; and the weight percentage of sodium lauryl sulfate is less
than or equal to 1.0% wt. Furthermore, the pure water and N,N-dimethyl acetamide used in the
present method are removed during preparation of the tablet and tile standard residual amount is
established to ensure the product quality (paragraph 0026). According to Example 1, a tablet
contains pure water, cross-linked sodium carboxymethyl cellulose, microcrystalline cellulose,
and magnesium stearate, among others (paragraph 0028).
The teachings of Lee and Bolen modified with Schwarz are related to sublingual tablets
and it would have been obvious to have combined them because they are in the same field of
endeavor. It would have been prima facie obvious to a person of ordinary skill in the art before
the effective filing date of the claimed invention to have formed Bolen's sublingual tablet
comprising cross-linked sodium carboxymethyl cellulose, mannitol, purified water, and
lubricant, with a reasonable expectation of success because Schwarz teaches forming a tablet
intended for sublingual administration, wherein the tablet comprises disintegrants such as crosscarmellose, sugars such as mannitol, and lubricants.
It would have been obvious to have selected magnesium stearate as the lubricant because
it was known from Lee that magnesium stearate is a suitable lubricant in tablets intended for
sublingual administration.
It would have been obvious to have formed the tablet by wet granulation using water
because Schwarz teaches forming the tablet by wet granulation and it was known from Lee that
tablets intended for sublingual administration may be formed by wet granulation using pure
water (paragraph 0029) where the final tablet contains pure water (paragraph 0028). Therefore, it
would have been obvious to have formed the tablet Bolen by wet granulation process using
water, where the final tablet comprises water.
Bolen' s tablet made in view of Schwarz and Lee meets all of the claimed limitations
because it contains cross-linked sodium carboxymethyl cellulose, mannitol, purified water, and
magnesium stearate.
Claim 30 is rejected under 35 U.S.C. 103 as being unpatentable over Bolen and Schwarz
as applied to claims 27 and 32-36 above, and further in view of Lee (2016/0375018 Al
Published December 29, 2016) and Soler Ranzani (US 2012/0283 262 A I Published November 8, 2012).
The claim encompasses the sublingual tablet of claim 28 and further define the
excipients.
The teachings of Bolen and Schwarz are relied upon as summarized above. They do not
teach sodium carboxymethyl cellulose and microcrystalline cellulose in the tablet.
The teachings of Lee are relied upon as summarized above.
The teachings of Lee and Bolen modified with Schwarz are related to sublingual tablets
and it would have been obvious to have combined them because they are in the same field of
endeavor. It would have been prima facie obvious to a person of ordinary skill in the art before
the effective filing date of the claimed invention to have formed Bolen' s sublingual tablet
comprising a diluent, polyvinyl pyrrolidone, mannitol, and lubricant, with a reasonable
expectation of success because Schwarz teaches forming a tablet intended for sublingual
administration, wherein the tablet comprises diluents (paragraph 0113), binders such as
polyvinylpyrrolidone, sugars such as mannitol, and lubricants.
It would have been obvious to have selected microcrystalline cellulose as the diluent
because it was known from Lee that microcrystalline cellulose is a suitable diluent in tablets
intended for sublingual administration.
It would have been obvious to have selected magnesium stearate as the lubricant
because it was known from Lee that magnesium stearate is a suitable lubricant in tablets intended
for sublingual administration.
Bolen modified in view of Schwarz and Lee does not teach sodium carboxymethyl
cellulose.
The teachings of Soler Ranzani are related to pharmaceutical compositions (Abstract),
including sublingual tablets (paragraph 0088). The compositions include excipients such as a
binder selected from water, carmellose sodium, and polyvinyl pyrrolidone (paragraph 0069).
It would have been obvious to have further modified Bolen's tablet by replacing
polyvinylpyrrolidone with sodium carboxymethyl cellulose (carmellose sodium), with a
reasonable expectation of success because it was known from Soler Ranzani that carmellose
sodium and polyvinylpyrrolidone are binders suitable for making sublingual tablets and
replacing one equivalent with another to obtain predictable results supports obviousness.
Bolen's tablet made in view of Schwarz, Lee, and SolerRanzani meets all of the claimed
limitations because it contains microcrystalline cellulose, sodium carboxymethyl cellulose,
mannitol, and magnesium stearate.
Response to Arguments
Applicant’s arguments submitted in the remarks dated June 12, 2026 were fully considered but are not persuasive for the following reasons.
Applicant’s argument that Bolen does verify whether other active agents besides siRNA and cholesterol-siRNA can be successfully encapsulated by exosomes, is not persuasive because exemplifying claimed active agents is not required in an obviousness rejection. Bolen’s teaching of peptide drugs such as insulin detemir is sufficient to render obvious an embodiment comprising insulin detemir encapsulated in milk exosomes as claimed. The skilled artisan would have been capable of making such encapsulated compositions through routine experimentation. Prior art references are not limited by exemplified embodiments, and a reference has to be considered for all of its teachings. The number of therapeutic agents disclosed by Bolen does not make any one therapeutic agent more or less obvious. All therapeutic agents would have been equally obvious to encapsulate.
It would have been obvious to have formulated the composition in a tablet form because Bolen teaches tablets. Bolen is not limited by exemplified compositions, thus it is irrelevant that all exemplified compositions are in liquid form. Bolen’s broadest teachings encompass tablet forms.
Argument’s against Schwarz are not persuasive because the reference was relied upon to show that sublingual administration is suitable for insulin and analogs therefore. The rejection is not based on a rationale that it would have been obvious to modify Bolen’s tablet by using Schwarz’ excipients and method of making a sublingual tablet. Bolen requires a drug encapsulated in milk exosomes and the skilled artisan would have been capable of selecting excipients and formulation steps in order to formulated Bolen’s milk exosomes comprising encapsulated drug as a sublingual tablet. The skilled artisan would have been aware that Bolen and Schwarz are distinct in terms of working principle and essential composition requirements, and in order to keep the drug encapsulated in the milk exosomes, the skilled artisan would have known how to select appropriate excipients and formulation conditions.
The teachings of Schwarz are not a teaching away from the presently claimed invention because the rejection is not based on a rationale that it would have been obvious to make Bolen’s tablet as self-emulsifying tablet. The skilled artisan would have been aware that the purpose of Bolen is to encapsulate the therapeutic agent and incorporated the encapsulated therapeutic agent into a sublingual tablet, thus the skilled artisan would not have followed the teachings of Schwarz to formulate the tablet.
Arguments that the liquid systems in Bolen cannot provide any teaching or reasonable expectation of success for tablet formulation is not persuasive because the rejection is not based on rationale that it would be obvious to convert Bolen’s liquid formulations into tablets.
Bolen at paragraph 0653 teaches that pharmaceutically acceptable compositions may be orally administered in any orally acceptable dosage form including tablets. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. Based on this teaching, it is apparent that Bolen teaches using excipients that are conventionally used to make tablets. The skilled artisan would have known which excipients to select in order to incorporate milk exosomes loaded with drug into a sublingual tablet. The purpose of Bolan is to deliver the drug in encapsulated form, thus the skilled artisan would have known how to select excipients and formulation methods in order to obtain a sublingual tablet that contains encapsulated drug.
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). All limitations and motivation to modify and combine references is present in the cited prior art.
Arguments that the claimed invention has unexpected properties are not persuasive because applicant has not met the requirements set forth in MPEP 716.02.
It is not clear why the applicant considers observed results unexpected. Liraglutide is a known drug for reducing blood glucose. Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected.
The applicant did not show that the results are statistically significant. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).
The claims are broader than the example of a sublingual tablet in Example 8. The applicant did not show that the asserted unexpected results would have occurred over the entire breadth of the claimed range. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range.
The nonobviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof.
Applicant did not compare the invention to the closest prior art. An affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. Applicants may compare the claimed invention with prior art that is more closely related to the invention than the prior art relied upon by the examiner.
Arguments against Lee and Soler Ranzani are not persuasive because Bolen and Schwarz are not deficient for reasons described above.
Conclusion
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 Alma - Pipic whose telephone number is (571)270-7459. The examiner can normally be reached M-F 9:00am-5:00pm. 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, Michael Hartley can be reached on 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300. Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ALMA PIPIC/
Primary Examiner, Art Unit 1617
Prosecution Insights