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 .
Claims 26, and 32-40 have been canceled. Claims 1-25, 27-31 and 41-46 have been amended and are examined on the merits.
Specification
The specification is objected to for referencing dosing information in figures 2, 4A and 4B (pages 34-35, paragraph [0103]). The specification does not contain a figure 4A or 4B and neither figure 2 nor figure 4 illustrates the dosing information referred to in the specification in paragraph [0103]..
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 1-25, 27-31 and 41-46 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.
(A)It is unclear if applicant intends the first, second, and fourth “predetermined period” referred to in claims 1 and 4 is part of the first treatment cycle, or subsequent treatment cycles.
(B)The recitation of a “predetermined period” in claims 1, 3 and 4 is vague and indefinite. Section 2171 of the M.P.E.P. states
Two separate requirements are set forth in 35 U.S.C. 112(b) and pre-AIA 35 U.S.C. 112, second paragraph, namely that:
(1) the claims must set forth the subject matter that the inventor or a joint inventor regards as the invention; and
(2) the claims must particularly point out and distinctly define the metes and bounds of the subject matter to be protected by the patent grant.
The first requirement is a subjective one because it is dependent on what the inventor or a joint inventor for a patent regards as his or her invention. Note that although pre-AIA 35 U.S.C. 112, second paragraph, uses the phrase "which applicant regards as his invention," pre-AIA 37 CFR 1.41(a) provides that a patent is applied for in the name or names of the actual inventor or inventors.
The second requirement is an objective one because it is not dependent on the views of the inventor or any particular individual, but is evaluated in the context of whether the claim is definite — i.e., whether the scope of the claim is clear to a hypothetical person possessing the ordinary level of skill in the pertinent art.
In the instant case, a “predetermined period” has no constraints as to hours, days, seeks or months and thus fails to particularly point out and distinctly define the metes and bounds of the subject matter to be protected by the patent grant.; and a “predetermined period” does not communicate to one of skill in the art what the inventor regards as the required period.
(C)The recitation of “particularly” in claims 6-22, 29, 30, is vague and infinite because it is unclear how qualifying a limitation as preferred “in particular” influences the metes and bounds of the claims.
(D)The recitation of “the at least one subsequent cycle” in claims 17-21 lacks specific antecedent basis in claim 1.
(E)The recitation of lymphoma in claim 28 and , non-Hodgkin’s lymphoma in claim 31 lacks specific antecedent basis in claim 1 which has been amended to exclude lymphoma.
(F)It is unclear if the “further comprising” in claims 41, 43, 45 and 46 refer to a method step in addition to the method steps of claim 1, or if applicant intends to narrow the scope of claim 1, If the later, “further comprising” should be “comprising”.
(G)The recitation of “a T cell engaging polypeptide construct” in claims 41, 43, 45 and 46 is vague and indefinite because it is unclear if this construct is the T cell engaging polypeptide construct of claim 1, or if “a” T cell engaging polypeptide construct refers to an alternative construct.. For purpose of examination, the “a T cell engaging construct” will be read as “the T cell engaging construct” in claims 41, 43 and 45.
(H)The recitation of “the subcutaneous administration scheme” in claim 29 lacks specific antecedent basis in claim 1.
(I)The recitation of “any of the preceding claims” in claim 29 lacks antecedent basis in claim 1 for claims other than claim 1.
(J)The recitation of “depicted” in SEQ ID NO: 3, 5, 7, and 9 in claim 27 is vague and indefinite because it is unclear if “depicted” includes a fragment of SEQ ID O: 3, 5, 7, or 9”, a sequence comprising SEQ ID O: 3, 5, 7, or 9” or a sequence consisting of SEQ ID NO: 3, 5, 7 or 9”.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-22, 25, 27-31, 41-46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
(A)The instant claims are reliant on a genus of T-cell engaging polypeptide construct binding to CD19 and comprising the CDRs of SEQ ID NO: 11-22. CD19 is not expressed by T cells, thus a portion of the CDRs must bind to an antigen on T cells in order to provide the “engagement”.
Section 2163 of the M.P.E.P. states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a “representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention.
In the instant case, absent a correlation with a specific antigen on a T cell that is bound by a paratope comprising some of the required CDR sequences, there is no correlation between the possession of the CDR sequences and binding/engaging a T cell. Amendment of claim 1 by incorporation of the limitations of claim 23 will overcome this rejection.
(B)Claim 29 is drawn in part to the method of claim 1 wherein the patient will be subjected to at least one further treatment preceding the subcutaneous administration. One cannot describe what has yet to occur regarding what the patient will or will not be subjected to in the future.
(C)Claims 41 and 44 are reliant on a genus of formulations for the subcutaneous administration of the T cell engager of claim 1. The specification describes two such formulations represented by claims 45 and 46. Claims 41-44 encompass formulations not defined by amounts of the required compounds or the H of the mixture of compounds. The description of the two formulations does not adequately describe the genus of formulations encompassed by the claims because the genus is highly variant with respect to the amounts of each composition and overall pH. The art teaches that the bioavailability of subcutaneously delivered BiTE® molecules is generally lower than that of intravenously delivered BiTE® molecules but this problem can be overcome by specific formulations that result in high bioavailability of BiTE® molecules upon subcutaneous delivery (Sharma et al, page 172, paragraph [00581]). In the instant case, there is no correlation between the presence of a specific compound or compounds at a particular level and a particular pH, and a functional attribute, such as resulting in higher bioavailability of the T cell engaging agent of claim 1. One of skill in the art would reasonably conclude that applicant was not in possession of the broad invention of claims 41-44 at the time of filing.
Claim Rejections - 35 USC § 103
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.
Claims 1-5, 7, 12, 16, 20, 21, 23-25, 27, and 28 are rejected under 35 U.S.C. 103 as being unpatentable over Sharma et al (WO2009/070642) as evidenced by Yang e al (WO2016/077505) in view of Sanford (Drugs, 2015, Vol. 75, pp. 321-327).
Sharma et al teach subcutaneous treatment with MEDI-538 prolongs the survival of mice engrafted with CD19+ Ramos B cell lymphoma cells (figure 36). Sharma et al teach that cohorts of 6 NOD/SCID mice were inoculated IV with 105 Ramos cells mixed with 5 x 106 human PBMCs (page 239, paragraph [00844]). Sharma et al teach that five daily doses of MEDI-538 were administered subcutaneously on days 1,2,3,4 and 5 (paragraph [00844] and Figure 36 with arrows indicating doses) which meets the limitations of claim 1 for at least two individual doses in a first quantity within the first predetermined period (for example, days 1 and 2) and at least two individual doses of a second quantity within a second predetermined period (days 3, 4 and 5).
It would have been prima facie obvious at the time prior to the effective filing date to provide an additional treatment cycle to that indicated in Figure 36 of Sharma et al, One of skill in the art would have been motivated to do so I order to obtaining an increased percentage of long term survivors. One of skill in the art have been motivated to start another treatment cycle which is identical to the first treatment cycle at around 30 days in order to prevent death by 40 days as indicated in Figure 36. This would meet the requirements of the treatment cycle being followed by at least one additional treatment cycle in claim 2; the third predetermined period which is a treatment free period which follows after day 5 in the first cycle, which meets the limitations of claim 3; the fourth predetermined period which is a treatment free period from after day 5 in cycle 2, which meets the limitation of claim 4; the first quantity being administered in 5 individual doses on one day which meets the limitation of claim 5; wherein the first quantity is 15ug meeting the limitation of claim 7; wherein the second predetermined period is two or three days, which meets the limitations of claim 12 and wherein the second quantity is administered 2-5 times weekly in claim 16, 20 and 21. Sharma et al teach that MEDI-538 is a CD19/CD3 specific BITE antibody (page 238, under table 14) which meets the limitations of claim 23. Sharma et al teach that MEDI-538 bound to human B cell tumor cells mixed with human PBMC (page 238, paragraph [00840]) which meets the limitation of human CD3 in claim 24 for binding to CD3 an the limitations of 25 because BITE antibodies are single-chain antibodies.
Yang et al provide evidence that MT-103 is also known as blinatumomab and has a VH sequence identical to the instant SEQ ID NO:3 and a VL sequence identical to the instant SEQ ID NO: 5 (page 163):
GenCore version 6.5.2
Copyright (c) 1993 - 2026 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: September 8, 2026, 05:07:45 ; Search time 1 Seconds
(without alignments)
0.015 Million cell updates/sec
Title: AASEQ1_09082026_010718
Perfect score: 663
Sequence: 1 QVQLQQSGAELVRPGSSVKI..........GRYYYAMDYWGQGTTVTVSS 124
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 124 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 50 summaries
Database : US-18-704-120A-3.fasta:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 663 100.0 124 1 US-18-704-120A-3 SUBCUTANEOUS ADMIN
ALIGNMENTS
RESULT 1
US-18-704-120A-3
Query Match 100.0%; Score 663; DB 1; Length 124;
Best Local Similarity 100.0%;
Matches 124; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIWPGDGDTNY 60
Qy 61 NGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTV 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 NGKFKGKATLTADESSSTAYMQLSSLASEDSAVYFCARRETTTVGRYYYAMDYWGQGTTV 120
Qy 121 TVSS 124
||||
Db 121 TVSS 124
and a VL sequence identical to the instant SEQ ID NO: 5 (page 163):
GenCore version 6.5.2
Copyright (c) 1993 - 2026 Biocceleration Ltd.
OM protein - protein search, using sw model
Run on: September 8, 2026, 05:12:02 ; Search time 1 Seconds
(without alignments)
0.012 Million cell updates/sec
Title: AASEQ1_09082026_011152
Perfect score: 590
Sequence: 1 DIQLTQSPASLAVSLGQRAT..........CQQSTEDPWTFGGGTKLEIK 111
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 111 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 50 summaries
Database : US-18-704-120A-5.fasta:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 590 100.0 111 1 US-18-704-120A-5 SUBCUTANEOUS ADMIN
ALIGNMENTS
RESULT 1
US-18-704-120A-5
Query Match 100.0%; Score 590; DB 1; Length 111;
Best Local Similarity 100.0%;
Matches 111; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVS 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 DIQLTQSPASLAVSLGQRATISCKASQSVDYDGDSYLNWYQQIPGQPPKLLIYDASNLVS 60
Qy 61 GIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK 111
|||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GIPPRFSGSGSGTDFTLNIHPVEKVDAATYHCQQSTEDPWTFGGGTKLEIK 111
Search completed: September 8, 2026, 05:12:02
Job time : 1 secs
Thus, the MEDI-538 of Sharma et al meets the limitations of comprising the CDR sequences of SEQ ID NO: 11-22 in claim 1, and the Vh of SEQ ID NO: 3 and the Vl of SEQ ID NO: 5 in claim 27.
Sharma et al teach that the bioavailability of subcutaneously delivered BiTE® molecules is generally lower than that of intravenously delivered BiTE® molecules but that the present invention provides BiTE® formulations that result in high bioavailability of BiTE® molecules upon subcutaneous delivery of the formulation (page 172, paragraph [00581]).
Sharma et al teach that PK characteristics in multiple animal models, provided sufficient systemic levels for efficacy against tumor challenge in xenograft mouse models, and depleted B cells in an immunocompetent mouse model and that, taken together, the data support the SC route of administration as an alternative method for delivery of MEDI-538 (page 239, paragraph [00841]).
Sharma et al do not teach the treatment of leukemia by subcutaneous administration of MEDI-538.
Sanford teaches that Blinatumomab is approved by the FDA for the treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (abstract).
It would have been prima facie obvious at the time prior to the effective filing date to test a mouse model of BCP-ALL with the MEDI-538, wherein the mice were implanted with human B cell leukemia cells using the method of Sharma et al and treated by subcutaneous injection. One of skill in the art would have been motivated to do so by the teachings of Sanford that the FDA granted approval to use Blinatumomab for the treatment of BCP-ALL thus meeting the limitation of a leukemia in claim 1 and the leukemia which is ALL in claim 28, and the teachings of Sharma et al that the SC route of administration of MEDI-538 in the inventive formulations, provides an alternative to the intravenous route.
All claims are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAREN A CANELLA whose telephone number is (571)272-0828. The examiner can normally be reached M-F 10-6:30.
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KAREN A. CANELLA
Examiner
Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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