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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/24/2025 has been entered.
Claims 102-106 and 111-121 are pending in this application and were examined on their merits.
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.
Claims 102-106 and 111-121 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. The metes and bounds of the claim with regard to the “lower concentration” cannot be readily determined because Claim 102 contains the following limitation:
“wherein the isolated recombinantly-expressed BBI, insulin, or a combination thereof, is provided in the oral composition at a lower concentration than would be therapeutically effective in an otherwise identical oral composition comprising a chemically-purified BBI instead of the isolated recombinantly-expressed BBI and achieving a comparable therapeutic effect in the subject”
Thus, the claim requires a comparison between two distinct compositions containing unspecified amounts of: insulin, any chelator of divalent cations, any other unspecified components (active or not) and; either an isolated rBBI or a chemically purified BBI.
The claim requires determination of a “comparable therapeutic effect” which may be any effect in any disorder or condition in any subject of any age, sex, weight, physical condition, etc. For purposes of examination, the Examiner has interpreted the claim as the oral composition being administered at any concentration. Claims 103-106 and 111-121 are rejected as being dependent upon rejected Claim 102.
Claim 102 recites the limitation "the subject" in Line 11. It is unclear of this refers the subject whom has been administered the oral composition comprising insulin, a chelator of divalent cations and an isolated rBBI or a different subject whom has been administered an oral composition comprising insulin, a chelator of divalent cations and a chemically purified BBI. That is, it cannot be determined it the same subject is administered both oral compositions or if two distinct subjects administered two distinct compositions.
The term “lower concentration” in Claim 102 is a relative term which renders the claim indefinite. The term “lower” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim Rejections - 35 USC § 103
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.
Claim(s) 102-106 and 111-121 are rejected under 35 U.S.C. § 103 as being
unpatentable over Hershko (WO 2013/114369 A1), cited in the IDS, in view of
Caccialupi et al. (2020), of record.
Hershko teaches an oral composition comprising the therapeutic protein insulin, the chelator of divalent cations EDTA and an isolated BBI, the use of the composition in
preparing a medicament for oral administration of a therapeutic protein to a subject and
orally administering the oral composition to a subject (Pg. 56, Claim 1, Pg. 57, Claims 13 and 14 and Pg. 59, Claims 32-33), and reading on Claim 102.
With regard to Claim 102, the reference further teaches that the BBI can be a
recombinant BBI (Pg. 9, Lines 5-7) and each capsule can contain 50-100 mg of isolated
BBI (Pg. 22, Lines 20-21).
The teachings of Hershko were discussed above.
Hershko did not teach wherein the isolated recombinantly-expressed BBI is expressed in a yeast expression system and the yeast expression system in Pichia pastoris, as required by Claim 102.
Caccialupi et al. teaches the recombinant expression of BBI in Pichia pastoris
(Pg. 1060, Paragraph 2.4).
It would have been obvious to those of ordinary skill in the art before the effective
filing date of the instant invention to modify the generic recombinant expression of the
BBI in the oral composition taught by Hershko with the expression of the recombinant
BBI in the Pichia pastoris expression system taught by Caccialupi et al. because this
would provide the artisan with a known and successfully used system for the production
of recombinant BBI. Those of ordinary skill in the art would have been motivated to
make this modification in order to produce the desired recombinant BBI. There would
have been a reasonable expectation of success in making this modification because
both references are drawn to the production and use of recombinant BBI.
With regard to Claims 104 and 105, the Hershko reference teaches the oral
composition further comprises the trypsin inhibitor KTI3 (Pg. 56, Claims 5-6).
With regard to Claim 106, the Hershko reference teaches the KTI3 has been
purified to at least 85% purity as measured by SDS-PAGE or purified to a protein
content of greater than 95% as measured by BCA assay (Pg. 56, Claims 7-8).
With regard to Claims 107 and 108, the Hershko reference teaches the
therapeutic peptide or protein is insulin (Pg. 57, Claim 12).
With regard to Claim 111, the Hershko reference teaches the chelator is EDTA
(Pg. 57, Claim 14).
With regard to Claim 112, the Hershko reference teaches the oral composition is
an oil-based liquid formulation (Pg. 56, Claim 1).
With regard to Claim 113, the Hershko reference teaches the oral composition
comprises a polyethylene glycol (PEG) ester of a monoglyceride, a diglyceride, a
triglyceride or a mixture thereof (Pg. 57, Claim 15).
With regard to Claim 114, the Hershko reference teaches the oil-based liquid
composition comprises glycerol (Pg. 58, Claim 18) and gelatin (Pgs. 58-59, Claims 28
and 30).
With regard to Claims 115 and 116, the Hershko reference teaches the oil-based
liquid composition comprises the non-ionic detergent polysorbate 80 (Pg. 58, Claims 23-
24).
With regard to Claim 117, the Hershko reference teaches the oil is a fish oil (Pg.
58, Claim 26).
With regard to Claim 118, the Hershko reference teaches the oil-based liquid
composition is water-free (Pg. 58, Claim 27).
With regard to Claims 119, 120 and 121, the Hershko reference teaches the oral
composition further comprises a pH-sensitive soft gelatin capsule that resists
degradation in the stomach (Pg. 58, Claim 28 and Pg. 59, Claim 29).
Response to Amendment
The Declaration under 37 CFR 1.132 filed 10/24/2025 is insufficient to overcome the rejection of claims 102-106 and 111-121 based upon 35 U.S.C. § 103 as set forth in the last Office action and above because:
The Declarant argues that purified Pichia pastoris recombinant BBI is
synergistically/surprisingly more effective than soybean BBI in enhancing the influence of oral insulin on blood glucose levels in experimental animals. Declarant notes that the tested experimental formulations contained: the divalent chelator EDTA in an amount of 150 mg, 8 mg insulin and either; 1) 100 mg SBTI, 70 mg BBI and 35 mg KTI, 2) 0 mg KTI, 100 mg RBBI and 0 mg SBTI, 3) 0 mg KTI, 50 mg RBBI and 0 mg SBTI or 4) 25 mg KTI, 100 mg RBBI and 0 mg SBTI.
The Declarant further cites the Specification at Pgs. 36-38, Example 4 wherein oral compositions containing: 1) 4 mg insulin and 150 mg EDTA and 2) 12.5 mg RBBI, 3) 25 mg RBBI, 4) 50 mg RBBI or 5) 75 mg RBBI were tested in animal models and the 3) and 5) formulations provide the greatest prolonged effect in reducing glucose levels (Declaration, Pgs. 2-3, #s 5-12).
This is not found to be persuasive for the following reasons, the experimental
compositions in the Declaration and the Specification are composed of: specific amounts of RBBI (with the alleged unexpected effect demonstrated at 50, 75 or 100 mg, with and without KTI), 150 mg EDTA and either 4 or 8 mg insulin, while the broad claim requires no specific amounts other than the undefined limitation that the oral composition comprising isolated recombinantly-expressed BBI, insulin and a chelator of divalent cations, or a combination thereof be provided "at a lower concentration than would be therapeutically effective in an otherwise identical oral composition comprising a chemically purified BBI" and does not require any particular amounts of the components. Thus, the experimental data are not commensurate in scope with the claimed invention. See the MPEP at 716.02(d).
Further, the data provided in the Declaration and Specification are not a comparison with the closest subject matter which exists in the prior art.
As noted above, Hershko teaches an oral composition comprising the therapeutic protein insulin, the chelator of divalent cations EDTA and an isolated BBI, the use of the composition in preparing a medicament for oral administration of a therapeutic protein to a subject and orally administering the oral composition to a subject. The reference further teaches that the BBI can be a recombinant BBI and each capsule can contain 50-100 mg of isolated BBI. Thus, the closest prior art would be the composition of Hershko comprising insulin, EDTA and 50-100 mg of recombinant BBI. See the MPEP at 716/02(e).
Finally, the Examiner notes that even if secondary considerations, such as a finding of unexpected results (indicia of non-obviousness) are established, the record may also establish such a strong case of obviousness that the objective evidence of nonobviousness is not sufficient to outweigh the evidence of obviousness. Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 769, 9 USPQ2d 1417, 1427 (Fed. Cir. 1988), cert. denied, 493 U.S. 814 (1989); Richardson-Vicks, Inc., v. The Upjohn Co., 122 F.3d 1476, 1484, 44 USPQ2d 1181, 1187 (Fed. Cir. 1997). In this instance, the only substantial difference between the primary reference and the claimed invention is the source of the recombinant BBI which is strongly obviated by Caccialupi.
Response to Arguments
Applicant's arguments filed 10/24/2025 have been fully considered but they are not persuasive.
The Applicant argues that Hershko and Caccialupi do not teach or suggest the claimed invention (Remarks, Pg. 7, Lines 4-8).
This is not found to be persuasive for the reasoning provided both in the prior action and above.
The Applicant argues that the rationale provided by the Examiner to support the conclusion of obviousness is allegedly insufficient under Office practice as it does not use one of the stated KSR rationales (Remarks, Pg. 7, Lines 9-19).
This is not found to be persuasive for the following reasons, while KSR rationales are available to the Examiner in supporting a conclusion of obviousness, they are not required for such a finding nor is it improper to use other rationales in a finding of obviousness. The Examiner notes that Hershko specifically teaches an embodiment BBI which is recombinantly produced.
The Applicant argues that while Caccialupi discloses recombinant BBI produced by Pichia pastoris (as claimed) the reference does not disclose the use thereof in therapeutics.
Applicant concludes that the ordinary artisan would have to select the general “recombinant BBI” from the BBI embodiments listed in Hershko and the particular recombinant species of Caccialupi and in view of the large number of possible choices it would not be a matter of selection from a finite number of identified, predictable solutions to arrive at the claimed invention and the Examiner’s motivation statement does not correct this deficiency (Remarks, Pg. 7, Lines 20-22 and Pg. 8, Lines 1-7).
This is not found to be persuasive for the following reasons, clearly Hershko discloses the therapeutic use of BBI inhibitors, as well as the general recombinant production of BBI inhibitors. Those of ordinary skill in possession of the general teaching of Hershko looking to recombinantly produce BBI inhibitor would look to Caccialupi whom teaches that BBI inhibitor may be recombinantly produced in P. pastoris. Thus, it would be a matter of selection from a finite number of identified, predictable solutions to arrive at the claimed invention with the motivated to make this modification being the recombinant production of the desired recombinant BBI. There would have been a reasonable expectation of success in making this modification because both references are drawn to the production and use of recombinant BBI.
The Applicant cites the second Declaration filed 10/24/2025 as demonstrating the alleged unexpected improved effect due solely to the source of BBI (Remarks, Pg. 8-10, Section B1).
This is not found to be persuasive for the reasoning provided above in the Response to Amendment. That is, the Declaratory data is not commensurate in scope with the claimed invention, is not a comparison with the closes cited prior art and may not be sufficient to overcome the strong prima facie case of obviousness.
The Applicant argues that KTI was not necessary in the composition to achieve the alleged unexpected results and asserts that the non-obviousness of a broader range can be supported by evidence based on unexpected results from a narrower range if the ordinary artisan could discern a trend in the data to reasonably extrapolate the probative value thereof. That is, the various tested formulations would allow the ordinary artisan to understand that any other amounts of insulin, EDTA or other divalent chelators) and RBBI could be used to prepare compositions with the same unexpected effects (Remarks, Pgs. 10-11, Section B2).
This is not found to be persuasive for the following reasons, the Examiner’s position is not that the presence of KTI makes the proffered data not commensurate in scope with the claimed invention or that other divalent chelators would not be expected to function in the composition. The Examiner’s position is that the proffered data is drawn to specific amounts of EDTA, insulin and RBBI while the claims are not merely drawn to a “broader range”, they are completely undefined and limitless.
Further, the Specification data at Example 4 indicated that of 4 tested compositions containing RBBI only two (25 and 75 mg) yielded the greatest prolonged effect in reducing glucose levels. Thus, at least this alleged unexpected effect could not be reasonable extrapolated to all values in the Example provided RBBI range.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to PAUL C MARTIN whose telephone number is (571)272-3348. The Examiner can normally be reached Monday-Friday 12pm-8pm EST.
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If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Sharmila G Landau can be reached at (571) 272-0614. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/PAUL C MARTIN/Examiner, Art Unit 1653 02/04/2026