www.uspto.gov
`
`UNITED STATES DEPARTMENT OF COMMERCE
`United States Patent and TrademarkOffice
`Address: COMMISSIONER FOR PATENTS
`P.O. Box 1450
`Alexandria, Virginia 22313-1450
`
`17/053,635
`
`11/06/2020
`
`Elizabeth Bray NORTON
`
`TU-000910US/TM-503
`
`5566
`
`Hyman IP Law
`1070 Green Street
`Suite 401
`San Francisco, CA 94133-3678
`
`OGUNBIYI, OLUWATOSIN A
`
`1645
`
`PAPER NUMBER
`
`NOTIFICATION DATE
`
`DELIVERY MODE
`
`09/08/2023
`
`ELECTRONIC
`
`Please find below and/or attached an Office communication concerning this application or proceeding.
`
`Thetime period for reply, if any, is set in the attached communication.
`
`Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
`following e-mail address(es):
`
`lhyman@ hymaniplaw.com
`
`PTOL-90A (Rev. 04/07)
`
`

`

`
`
`Disposition of Claims*
`1-8,10-12,16,19-20,30-33,37,39-40,48,59 and 61 is/are pending in the application.
`)
`Claim(s)
`5a) Of the above claim(s) 1-8,10-12,16 and 19-20 is/are withdrawn from consideration.
`[) Claim(s)__ is/are allowed.
`Claim(s) 30-33,37,39-40,48,59 and 61 is/are rejected.
`(1 Claim(s)__is/are objectedto.
`C] Claim(s)
`are subjectto restriction and/or election requirement
`“If any claims have been determined allowable, you maybeeligible to benefit from the Patent Prosecution Highway program at a
`participating intellectual property office for the corresponding application. For more information, please see
`http:/Awww.uspto.gov/patents/init_events/pph/index.jsp or send an inquiry to PPHfeedback@uspto.gov.
`
`) ) ) )
`
`Application Papers
`10) The specification is objected to by the Examiner.
`11)() The drawing(s) filedon__ is/are: a)C) accepted or b)C) objected to by the Examiner.
`Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1.85(a).
`Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121 (d).
`
`Priority under 35 U.S.C. § 119
`12). Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 119(a)-(d) or (f).
`Certified copies:
`cc) None ofthe:
`b)L) Some**
`a)D) All
`1.(.) Certified copies of the priority documents have been received.
`2.1) Certified copies of the priority documents have been received in Application No.
`3.2.) Copies of the certified copies of the priority documents have been receivedin this National Stage
`application from the International Bureau (PCT Rule 17.2(a)).
`* See the attached detailed Office action for a list of the certified copies not received.
`
`Attachment(s)
`
`1)
`
`Notice of References Cited (PTO-892)
`
`2) (J Information Disclosure Statement(s) (PTO/SB/08a and/or PTO/SB/08b)
`Paper No(s)/Mail Date
`U.S. Patent and Trademark Office
`
`3)
`
`(LJ Interview Summary (PTO-413)
`Paper No(s)/Mail Date
`4) (J Other:
`
`PTOL-326 (Rev. 11-13)
`
`Office Action Summary
`
`Part of Paper No./Mail Date 20230814
`
`Application No.
`Applicant(s)
`17/053,635
`NORTON etal.
`
`Office Action Summary Art Unit|AIA (FITF) StatusExaminer
`OLUWATOSIN A OGUNBIYI
`1645
`Yes
`
`
`
`-- The MAILING DATEof this communication appears on the cover sheet with the correspondence address --
`Period for Reply
`
`A SHORTENED STATUTORY PERIOD FOR REPLYIS SET TO EXPIRE 3 MONTHS FROM THE MAILING
`DATE OF THIS COMMUNICATION.
`Extensions of time may be available underthe provisions of 37 CFR 1.136(a). In no event, however, may a reply betimely filed after SIX (6) MONTHSfrom the mailing
`date of this communication.
`If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHSfrom the mailing date of this communication.
`-
`- Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133).
`Any reply received by the Office later than three months after the mailing date of this communication, evenif timely filed, may reduce any earned patent term
`adjustment. See 37 CFR 1.704(b).
`
`Status
`
`1) Responsive to communication(s) filed on 6/27/23.
`C} A declaration(s)/affidavit(s) under 37 CFR 1.130(b) was/werefiled on
`
`2a)() This action is FINAL. 2b)¥)This action is non-final.
`3)02 An election was madeby the applicant in responseto a restriction requirement set forth during the interview
`on
`; the restriction requirement and election have been incorporated into this action.
`4)\0) Since this application is in condition for allowance except for formal matters, prosecution as to the merits is
`closed in accordance with the practice under Exparte Quayle, 1935 C.D. 11, 453 O.G. 213.
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 2
`
`Notice of Pre-AIA or AIA Status
`
`The present application, filed on or after March 16, 2013, is being examined under
`
`the first inventorto file provisions of the AIA.
`
`Response to Amendment
`
`The amendmentfiled 6/27/23 has been entered. Claims 1-8, 10-12, 16 and 19-20
`
`are withdrawn. Claims 30-33, 37, 39-40, 48, 59 and 61 are pending and are under
`
`examination.
`
`Claim Rejections Withdrawn
`
`The rejection of claim 39 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-ATA),
`
`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 is withdrawn in view
`
`of the amendmentto the claim.
`
`The rejection of claims 30-33 and 48 under 35 U.S.C. 103 as being unpatentable
`
`over Clements, John (hereinafter “Clements”) US 2003/0113345 June 19, 2003 cited in
`
`IDS in view of Baudier, R., (hereinafter “Baudier”), “Research Funding Extended for
`
`E112K as novel Therapy for IBD”. Norton Lab Website., 1/20/2017, Tulane Med Sch,
`
`New Orleans, LA, US. Accessed 9/5/2019, cited in IDS and Fakhouryetal. Journal of
`
`Inflammation Research, 2014; 7:113-120 1s withdrawnin view of the showing of
`
`evidence of secondary consideration in the specification in that E112K mutant was shown
`
`to be an effective therapy for IBD in three different mouse modelsofcolitis.
`
`The rejection of claims 30-32, 37, 39 and 48 under 35 U.S.C. 103 as being
`
`unpatentable over Baudier, R., (hereinafter “Baudier”), “Research Funding Extended for
`
`E112K as novel Therapy for IBD”. Norton Lab Website., 1/20/2017, Tulane Med Sch,
`
`New Orleans, LA, US. Accessed 9/5/2019, cited in IDS in view of Fakhouryetal.
`
`Journal of Inflammation Research, 2014; 7:113-120 and Kelly et al. Journal of Drug
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 3
`
`Delivery. Vol. 22, Article ID 727241, 11 pages, doi:10.1155/2011/727241 is withdrawn
`
`in view of the showing of evidence of secondary consideration in the specification in that
`
`E112K mutant was shownto be an effective therapy for IBD in three different mouse
`
`modelsof colitis.
`
`The rejection of claims 30-32, 40 and 48 under 35 U.S.C. 103 as being
`
`unpatentable over Baudier, R., (hereinafter “Baudier”), “Research Funding Extended for
`
`E112K as novel Therapy for IBD”. Norton Lab Website., 1/20/2017, Tulane Med Sch,
`
`New Orleans, LA, US. Accessed 9/5/2019, cited in IDS in view of Fakhouryetal.
`
`Journal of Inflammation Research, 2014; 7:113-120 and Baertet al. International Journal
`
`of Nanomedicine 2016:11 2463-2469 is withdrawnin view of the showing of evidence of
`
`secondary consideration in the specification in that E112K mutant was shown to be an
`
`effective therapy for IBD in three different mouse models ofcolitis.
`
`The rejection of claims 59 and 61 under 35 U.S.C. 103 as being unpatentable over
`
`Clements, John (hereinafter “Clements”) US 2003/0113345 June 19, 2003 cited in IDS in
`
`and Baudier, R., (hereinafter “Baudier”), “Research Funding Extended for E112K as
`
`novel Therapy for IBD”. Norton Lab Website., 1/20/2017, Tulane Med Sch, New
`
`Orleans, LA, US. Accessed 9/5/2019, cited in IDS and Fakhouryetal. Journal of
`
`Inflammation Research, 2014; 7:113-120 as applied to claims 30-33 and 48, further in
`
`view of Raz et al. US 7,560,436 7/14/09 is withdrawn in view of the showing of evidence
`
`of secondary consideration in the specification in that E112K mutant was shownto be an
`
`effective therapy for IBD in three different mouse models ofcolitis.
`
`The rejection of claims 59 and 61 under 35 U.S.C. 103 as being unpatentable over
`
`Baudier, R., (hereinafter “Baudier”), “Research Funding Extended for E112K as novel
`
`Therapy for IBD”. Norton Lab Website., 1/20/2017, Tulane Med Sch, New Orleans, LA,
`
`US. Accessed 9/5/2019, cited in IDS and Fakhouryetal. Journal of Inflammation
`
`Research, 2014; 7:113-120 and Kelly et al. Journal of Drug Delivery. Vol. 22, Article ID
`
`727241, 11 pages, doi: 10.1155/2011/727241 as applied to claims 30-32, 37, 39 and 48,
`
`further in view of Raz et al. US 7,560,436 7/14/09 is withdrawnin view of the showing
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 4
`
`of evidence of secondary consideration in the specification in that E112K mutant was
`
`shownto be an effective therapy for IBD in three different mouse modelsofcolitis.
`
`The rejection of claims 59 and 61 under 35 U.S.C. 103 as being unpatentable over
`
`Baudier, R., (hereinafter “Baudier”), “Research Funding Extended for E112K as novel
`
`Therapy for IBD”. Norton Lab Website., 1/20/2017, Tulane Med Sch, New Orleans, LA,
`
`US. Accessed 9/5/2019, cited in IDS and Fakhouryet al. Journal of Inflammation
`
`Research, 2014; 7:113-120 and Baertet al. International Journal of Nanomedicine
`
`2016:11 2463-2469 as applied to claims 30-32, 40 and 48, further in view of Razetal.
`
`US 7,560,436 7/14/09 is withdrawn in view of the showing of evidence of secondary
`
`consideration in the specification in that E112K mutant was shownto be an effective
`
`therapy for IBD in three different mouse models ofcolitis.
`
`The rejection of claims 30-32 and 48 under 35 U.S.C. 103 as being unpatentable
`
`over Baudier, R., (hereinafter “Baudier’’), “Research Funding Extended for E112K as
`
`novel Therapy for IBD”. Norton Lab Website., 1/20/2017, Tulane Med Sch, New
`
`Orleans, LA, US. Accessed 9/5/2019, cited in IDS in view of Fakhouryet al. Journal of
`
`Inflammation Research, 2014; 7:113-120 1s withdrawnin view of the showing of
`
`evidence of secondary consideration in the specification in that E112K mutant was shown
`
`to be an effective therapy for IBD in three different mouse modelsofcolitis.
`
`The rejection of claims 59 and 61 under 35 U.S.C. 103 as being unpatentable over
`
`Baudier, R., (hereinafter “Baudier”), “Research Funding Extended for E112K as novel
`
`Therapy for IBD”. Norton Lab Website., 1/20/2017, Tulane Med Sch, New Orleans, LA,
`
`US. Accessed 9/5/2019, cited in IDS and Fakhouryet al. Journal of Inflammation
`
`Research, 2014; 7:113-120 as applied to claims 30-32, and 48, further in view of Razet
`
`al. US 7,560,436 7/14/09 is withdrawnin view of the showing of evidence of secondary
`
`consideration in the specification in that E112K mutant was shownto be an effective
`
`therapy for IBD in three different mouse models ofcolitis.
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 5
`
`New Claim Rejections
`
`The following is a quotation ofthe first paragraph of 35 U.S.C. 112(a):
`
`(a) INGENERAL.—Thespecification shall contain a written description of the invention, and
`of the manner and process of making andusingit, 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
`makeand use the same, and shall set forth the best mode contemplated by the inventororjoint inventor
`of carrying out the invention.
`
`The following is a quotation ofthe 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 usingit, 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 30-33, 37, 39-40, 59 and 61 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 wasnotdescribed in
`
`the specification in such a wayas to reasonably conveyto 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 wasfiled, had possession of the claimed
`
`invention. This is a written description rejection.
`
`The claims are drawn to a method of reducing symptomsof inflammation in a
`
`subject in need thereof, said method comprising administering to said subject a
`
`composition comprising a therapeutically effective amountof: (a) (4) an E. coli heat labile
`
`enterotoxin (“LT”) non-toxic A subunit which inhibits ADP-ribosylation inacell
`
`pretreated with said non-toxic A subunit whensaid cell is then contacted with E. coli LT
`
`holotoxin, (11) a LT non-toxic Al subunit which inhibits ADP-ribosylation in a cell
`
`pretreated with said non-toxic A subunit whensaid cell is then contacted with E. coli LT
`
`holotoxin,or, (111) a combination of said non-toxic A subunit and said non-toxic Al
`
`subunit, and, (b) a carrier which causesinternalization of said non-toxic A subunit or
`
`non-toxic Al subunit, or combination thereof, into cells, wherein said inflammation is
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 6
`
`inflammatory bowel disease, optionally wherein said inflammatory boweldisease is
`
`ulcerative colitis or Crohn’s disease.
`
`The claims require a genus of LT non-toxic A subunit and LT non-toxic Al
`
`subunit and the common function of members of said genus is that they have the activity
`
`of inhibiting ADP-ribosylation in a cell pre-treated with said non-toxic A or Al subunit
`
`when said non-toxic A or Al subunit whensaid cell is then contacted with E. coli LT
`
`holotoxin.
`
`A composition comprising said LT non-toxic A or Al subunit which hassaid
`
`activity of inhibiting ADP-ribosylation and said carrier are used for reducing symptoms
`
`of inflammatory bowel disease (IBD) in a subject in need thereof, optionally wherein said
`
`IBD is ulcerative colitis or Crohn’s disease.
`
`E. coli heat labile enterotoxin (LT) has an ABsstructure with covalently A and B
`
`subunits. The A subunit causes the toxic effects of the holotoxin, while the B (“binding”)
`
`subunit is responsible for cellular binding and internalization. The A subunitis
`
`susceptible to cleavage by trypsin resulting in the Al subunit or domain. Thus, the Al
`
`subunit or domain is comprised in the A subunit of LT. Apart from the native B subunit
`
`for causing internalization, the specification proposes that other carriers that can cause
`
`internalization into a cell can be paired with the non-toxic LT A or Al subunit or
`
`combination thereof to cause internalization of the non-toxic LT A or Al subunit or
`
`combination thereof. See paragraph 43 and 54-58 of the specification.
`
`Escherichia coli heat-labile enterotoxin CLT) exerts its effects on eukaryotic celis
`
`through the ADP-ribosylation of guanine nucleotide-binding proteins of the adenylate
`
`cyclase complex. Introduction of substitutions al potential active site residues of LT have
`
`revealed residues such as serine 61 (S61), glutamic acid 110 (£110) and glutamic acid
`
`112 (E112) fave resulied in reduction of the toxic ADP nbosylation activity to less than
`
`10%of wild type levels. See Crepiak et al. Journal of Biological Chemistry, Vol. 270,
`
`Issue 51, 22 December 1995, pages 30545-35450.
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 7
`
`LTis a clinically important cause of traveler’s diarrhea and there has been studies
`
`exemplifying the use of LT and detoxified LT including detoxified A or Al subunits as
`
`vaccinesor as adjuvants. See specification at paragraph 31 and US Patent No. 8,110,197.
`
`Applicants reduce to practice in the example E112K which is a mutated LT
`
`holotoxin with substitution of lysine K for a glutamic acid, E at position 112 of the LT A
`
`subunit. See paragraph 38. Thus, E112K comprisesthe native B subunitas the carrier.
`
`The experimentdescribed in the specification disclose that cells pretreated with
`
`E112K and then contacted with native holotoxin did not exhibit ADP-ribosylation and the
`
`inference is that the E112K composition binds ADPribosylation factor (ARF), thereby
`
`interfering with or blocking its ADP ribosylation activity. See example 4 of the
`
`specification. Thus, E112K which has reduced ADPribosylation activity can inhibit
`
`ADPribosylation by E. coli holotoxin in a cell pre-treated with said E112K.
`
`The specification teaches that a detoxified A subunit that inhibit ADP ribosylation
`
`is useful an anti-inflammatory agentbut not useful as an adjuvant to enhance an immune
`
`response.
`
`The specification does not disclose any other detoxified LT toxin or any other
`
`detoxified A or A 1 subunit that inhibits ADP ribosylation in a cell pretreated with said
`
`non-toxic A subunit whensaid cell is then contacted with E. coli holotoxin.
`
`The disclosure of the E112K andits ability to inhibit ADP ribosylation does not
`
`put Applicants in possession of the genus of detoxified LT toxin or any other detoxified
`
`A or Al subunit that inhibits ADP ribosylation in a cell pretreated with said non-toxic A
`
`or Al subunit when said cell is then contacted with E. coli holotoxin.
`
`The specification proposes a theory that the mutated Al subunit of E112K is
`
`released into the cytosol upon internalization and that it is the mutated Al subunit of
`
`E112Kthat interferes with the function of ADP ribosylation factor (ARF) and thatit is
`
`the interference of the Al- subunit with ARFactivity that inhibits ongoing vesicular
`
`trafficking and innate signaling (e.g. IL-6 cytokine secretion) and decreases cAMPlevels
`
`over time, ultimately dampening overall levels of inflammation.
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 8
`
`While the specification predicts other non-toxic mutants of the Al domain shares
`
`the properties of E112K (see paragraph 48-50), there is no practical evidencethat other
`
`detoxified mutants inhibits ADP ribosylation in a cell pretreated with said non-toxic A
`
`subunit when said cell is then contacted with E. coli holotoxin. There is no correlation
`
`betweenstructure of these other detoxified LT mutants having mutation in the Al or A
`
`subunit and the function of inhibiting ADP ribosylation in a cell pretreated with said
`
`non-toxic A or Al subunit when said cell is then contacted with E. coli holotoxin.
`
`The disclosure of E112K 1s not representative of the genusof detoxified LT toxins
`
`or detoxified A or Al subunits that have the function of inhibiting ADP ribosylation in
`
`a cell pretreated with said non-toxic A subunit whensaid cell is then contacted with E.
`
`coli holotoxin.
`
`A "representative numberof species" meansthat the species which are adequately
`
`described are representative of the entire genus. Thus, whenthere is substantial variation
`
`within the genus, one must describe a sufficient variety of species to reflect the variation
`
`within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc.,
`
`759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claimsdirected to a
`
`functionally defined genus of antibodies were not supported by a disclosure that "only
`
`describe[d] one type of structurally similar antibodies" that "are not representative of the
`
`full variety or scope of the genus.").
`
`In the instant case, the specification states that other detoxified Al or Al subunits
`
`with mutations such as but not limiting to substitutions at residues E112, E110, R25, S61
`
`can be tested for inhibition of ADP ribosylation, in a cell pre-treated with said non-toxic
`
`A or Al subunit whensaid cell is then contacted with E. coli LT holotoxin.
`
`However, possession may not be shown by merely describing how to obtain
`
`possession of membersof the claimed genusor how to identify their commonstructural
`
`features. See University ofRochester, 358 F.3d at 927, 69USPQ2dat 1895. The written
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 9
`
`description provision of 35 U.S.C. § 112 are severable from its enablement provision
`
`Vas-Cath, Inc. v. Mahurkar, 1115.
`
`The specification teaches that a detoxified A or Al subunit that inhibit ADP
`
`ribosylation is useful as an anti-inflammatory agent but not useful as an adjuvantto
`
`enhance an immuneresponse(paragraph 31). It is noted that detoxified A or Al subunits
`
`detoxified at certain residues have adjuvantactivity andit is not clear without further
`
`testing whether such mutants also possess anti-inflammatory activity and are able to
`
`inhibit ADP ribosylation in a cell pre-treated with said non-toxic A or Al subunit when
`
`said cell is then contacted with E. coli LT holotoxin.
`
`U.S. Patent 8110197 (Hsu et al) teaches that S61 LT mutants having mutationsin
`
`the Al/A subunit such as S61K, S61R, S61F, S61H, S61Y mutant are detoxified and lack
`
`ADPribosylation activity as compared to wildtype LT. See table 2., Hsu et al disclose
`
`these mutants are adjuvants. Thus, further testing would be required to see whether
`
`these non-toxic mutants have the function of inhibiting ADP ribosylation in a cell
`
`pretreated with said non-toxic A or Al subunit whensaid cell is then contacted with E.
`
`coli holotoxin.
`
`The specification discloses a detoxified A subunit that inhibit ADP ribosylation is
`
`useful an anti-inflammatory agent but not useful as an adjuvant to enhance an immune
`
`response. However, regarding E112K mutant, one study has shown that this mutant has
`
`adjuvant properties and another showed that E112K lacked adjuvantactivity. For
`
`instance, the E112K when co-administered with keyhole limpet hemocyanin byan oral
`
`route lacked adjuvant properties and in another scenario, the activity of the E112K was
`
`found to be identical to that of the LT holotoxin when delivered with a different antigen
`
`1.e. influenza virus surface antigen by an intranasal route. See Park et al. Experimental
`
`and Molecular Medicine, Vol. 31, No. 2, 101-107, June 1999 page 101 left column to
`
`page 102 right hand column lines 1-3.
`
`Thus, based on the disclosure that a detoxified A subunit that inhibit ADP
`
`ribosylation is useful an anti-inflammatory agent but not useful as an adjuvant to enhance
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 10
`
`an immuneresponse, the inflammatory property of E112K which can act as adjuvantin
`
`some cases, was not discovered until further testing for inhibition of ADP ribosylation in
`
`a cell pretreated with said E112K whensaid cell is then contacted with E. coli holotoxin.
`
`Thus,it is possible that non-toxic A or Al subunits that are adjuvants could also
`
`be anti-inflammatory, despite the specification stating that a detoxified A subunit that
`
`inhibits ADP ribosylation is useful an anti-inflammatory agentbut not useful as an
`
`adjuvant to enhance an immune response
`
`It will require further testing to see whether the other non-toxic mutants whichare,
`
`for example, adjuvants, for example, disclosed by Hsuet al also possess anti-
`
`inflammatory properties. Possession of adjuvant activity may not excludeanti-
`
`inflammatory activity as evidenced by E112K.Clearly, the anti-inflammatory activity of
`
`non-toxic mutants may not be extrapolated to other mutants without further experiments.
`
`The E112K mutantis not representative of the entire genus of non-toxic Al or A subunits
`
`that inhibit ADP ribosylation in a cell pre-treated with said non-toxic A or Al subunit
`
`whensaid cell is then contacted with E. coli LT holotoxin.
`
`Applicants only have a research plan to discover other non-toxic Al or non-toxic
`
`A subunits that inhibit ADP ribosylation in a cell pre-treated with said non-toxic A or Al
`
`subunit when said cell is then contacted with E. coli LT holotoxin, and in combination
`
`with a carrier that causes internalization of said non-toxic subunits a can be used to
`
`reduce symptomsofinflammatory bowel disease which encompassesulcerative colitis or
`
`Crohn’s disease.
`
`With the written description of a genus, however, merely drawing a fence around
`
`a perceived genusis not a description of the genus
`
`
`. Otherwise, one has only a research plan,
`leaving it to others to explore the unknown contoursof the claimed genus. See Ariad, 598
`
` F.3d at 1353
`
`
`

`

`Application/Control Number: 17/053,635
`Art Unit: 1645
`
`Page 11
`
`
`
`Abbvie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111
`
`U.S.P.Q.2d 1780, 1790, 2014 BL 183329, 12 (Fed. Cir. 2014).
`
`In view of the above considerations, Applicants wereas of the effective filing date
`
`only in possession of non-toxic E112K mutant that inhibits ADP ribosylation inacell
`
`pre-treated with said non-toxic A subunit when said cell is then contacted with E. coli LT
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`holotoxin. Applicants were not in possession of the full genus of non-toxic Al or non-
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`toxic A subunit or combination thereof that inhibits ADP ribosylation in a cell pre-
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`treated with said non-toxic A subunit when said cell is then contacted with E. coli LT
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`holotoxin. Therefore,
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`the claims do not comply with the written description requirement.
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`Claims 30-33, 37, 39-40, 48, 59 and 61 are rejected under 35 U.S.C. 112(a) or
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`35 U.S.C. 112 (pre-AIA), first paragraph, because the specification, while being enabling
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`for a method of reducing symptomsof inflammatory bowel disease optionally ulcerative
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`colitis or Crohn’s disease in a subject in need thereof, said method comprising
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`administering to said subject a composition comprising a therapeutically effective amount
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`of non-toxic E. coli heat labile enterotoxin comprising mutation in the Al or A subunit
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`wherein the mutation is E112K and a carrier which causes internalization of said E112K
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`mutant wherein said E112K non-toxic mutant inhibits ADP ribosylation in a cell pre-
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`treated with said E112K mutant whensaid cell is then contacted with E. coli LT
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`holotoxin;
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`does not reasonably provide enablement for a method of reducing symptomsof
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`inflammatory bowel disease optionally ulcerative colitis or Crohn’s disease in a subject in
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`need thereof, said method comprising administering to said subject a composition
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`comprising a therapeutically effective amount of any other E. coli heat labile enterotoxin
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`(LT) non-toxic A subunit which inhibits ADP ribosylation in a cell pre-treated with said
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`

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`Application/Control Number: 17/053,635
`Art Unit: 1645
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`Page 12
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`non-toxic A subunit whensaid cell is then contacted with E. coli LT holotoxin or LT
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`non-toxic Al subunit which inhibits ADP ribosylation in a cell pre-treated with said non-
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`toxic Al subunit whensaid cell is then contacted with E. coli LT holotoxin or
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`combination thereof s; and a carrier which causesinternalization of said any other non-
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`toxic A or Al subunit or combination thereof.
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`The specification is not enabling for any other E. coli heat labile enterotoxin (LT)
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`non-toxic A subunit which inhibits ADP ribosylation in a cell pre-treated with said non-
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`toxic A subunit when said cell is then contacted with E. coli LT holotoxin and the
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`specification is not enabling for any other E. coli heat labile enterotoxin (LT) non-toxic
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`Al subunit which inhibits ADP ribosylation in a cell pre-treated with said non-toxic Al
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`subunit when said cell is then contacted with E. coli LT holotoxin.
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`The specification does not enable any person skilled in the art to whichit pertains,
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`or with whichit is most nearly connected, to use the invention commensurate in scope
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`with these claims. This is a scope of enablementrejection.
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`Enablementis considered in view of the Wands factors (MPEP 2164.01(A)).
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`These include: nature of the invention, breadth of the claims, guidance of the
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`specification, the existence of working examples,state of the art, predictability of the art
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`and the amountof experimentation necessary. All of the Wands factors have been
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`considered with regard to the instant claims, with the most relevant factors discussed
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`below.
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`The claims are drawn to:
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`A method of reducing symptomsof inflammation in a subject in need thereof, said
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`method comprising administering to said subject a composition comprising a
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`therapeutically effective amountof: (a) (i) an E. coli heat labile enterotoxin (“LT”) non-
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`toxic A subunit which inhibits ADP-ribosylation in a cell pretreated with said non-toxic
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`A subunit when said cell is then contacted with E. coli LT holotoxin, (11) a LT non-toxic
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`Al subunit which inhibits ADP-ribosylation in a cell pretreated with said non-toxic A
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`

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`Application/Control Number: 17/053,635
`Art Unit: 1645
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`Page 13
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`subunit when said cell is then contacted with E. coli LT holotoxin, or, (111) a combination
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`of said non-toxic A subunit and said non-toxic Al subunit, and, (b) a carrier which causes
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`internalization of said non-toxic A subunit or non-toxic Al subunit, or combination
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`thereof, into cells, wherein said inflammation is inflammatory bowel disease, optionally
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`wherein said inflammatory boweldisease is ulcerative colitis or Crohn’s disease.
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`The breadth of the claims encompassthe use of E. coli heat labile enterotoxin (LT)
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`non-toxic A subunit which inhibits ADP ribosylation in a cell pre-treated with said non-
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`toxic A subunit whensaid cell is then contacted with E. coli LT holotoxin or the use of E.
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`coli heat labile enterotoxin (LT) non-toxic Aa subunit which inhibits ADPribosylation
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`in a cell pre-treated with said non-toxic Al subunit when said cell is then contacted with
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`E. coli LT holotoxin.
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`Said non-toxic A subunit or non-toxic Al subunit with the properties regarding
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`inhibition of ADP ribosylation encompass non-toxic mutants with mutationsat residues
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`E112, E110, S61 or R25. See page 4 lines 2-6.
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`Escherichia coli heat-labile enterotoxin (LT) exerts us effects on cukaryotic cells
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`through the ADP-ribosylation of guanine nucleotide-binding protems ofthe adenylate
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`cyclase complex. Introduction of substitutions at potential active site residues of LT have
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`revealed residues such as serme 61 (S61), glutamic acid 110 C2110) and glutamic acid
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`L12 (E112) have resulted in reduction of the toxic ADP ribosylation activily to less than
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`10%of wild type levels. See Ciepiak et al. Journal of Biological Chemistry, Vol. 270,
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`issue S1, 22 December 1995, pages 30545-35550.
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`LTis a clinically important cause oftraveler’s diarrhea and there has been studies
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`exemplifying the use of LT and detoxified LT including detoxified A or Al subunits as
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`vaccinesor as adjuvants. See specification at paragraph 31 and US Patent No. 8,110,197.
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`The specification teaches that a detoxified A subunit that inhibit ADP ribosylation
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`is useful an anti-inflammatory agentbut not useful as an adjuvant to enhance an immune
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`response.
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`Application/Control Number: 17/053,635
`Art Unit: 1645
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`Page 14
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`Applicants reduce to practice in the example E112K whichis a mutated LT
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`holotoxin with substitution of lysine K for a glutamic acid, E at position 112 of the LT A
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`subunit. See paragraph 38. Thus, E112K comprisesthe native B subunitas the carrier.
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`The experimentdescribed in the specification disclose that cells pretreated with
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`E112K and then contacted with native holotoxin did not exhibit ADP-ribosylation and the
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`inferenceis that the E112K composition binds ADPribosylation factor (ARF), thereby
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`interfering with or blocking its ADP ribosylation activity. See example 4 of the
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`specification. Thus, E112K which has reduced ADPribosylation activity can inhibit
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`ADPribosylation by E. coli holotoxin in a cell pre-treated with said E112K.
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`The specification states that in view of these results, it is believed that this mutant
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`E112K and other detoxified A subunits that likewise interfere with ARF intracellular
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`function and inhibit ADP ribosylation will also inhibit the activation of dendritic cells,
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`reduce acute and chronic inflammation, including inflammatory T cell activity and
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`improves symptomsof IBD. See paragraph 26 and 47.
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`The exemplary construct used in the working examples is the E112K mutant
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`whichis the A subunit of E. coli labile toxin with an E112K mutation, tethered through
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`the A2 domain to an ETEC LT B subunit. The tethered B subunitacts as the carrier to
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`allow internalization of the mutant LT toxin into dendritic cells. See paragraph 47 of the
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`specification.
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`The specification teaches that E112K has (1) no ability to ADP ribosylate host
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`receptor proteins, (2) no ability to induce intracellular cAMP in epithelial cells and (3) no
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`ability to act as a robust adjuvant for co-administered antigens. The specification teaches
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`that E112K had a surprisingly different effect on the