DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant’s amendment filed on May 19, 2026 is acknowledged.
Claims 1-76 have been canceled.
Claims 77-92 have been added.
Claims 77-92 are pending.
Claims 90-92 have been withdrawn under 37 CFR 1.142(b) as being drawn to nonelected invention.
Claims 77-89 are currently under consideration as they read on the elected invention of a homodimeric stradomer unit comprising at least one homodimeric IgG1 Fc comprising two Fc monomers, each comprising a T299A, E345R, E430G, and S440Y substitutions and corresponding amino acid sequence of SEQ ID NO:32.
3. In view of applicant’s amendment, following rejections are set forth.
4. 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 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.
5. 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.
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.
6. Claims 77-89 stand rejected under 35 U.S.C. 103 as being unpatentable over Block et al. (WO/2012016073, reference on IDS) in view of Wittrup et al. (US 8,815,237, reference of record), Reye et al. (2012/0100140, reference on IDS), and Diebolder et al. (Science 2014 March 14; 343(6176):1260-1263, reference on IDS) for the reasons of record.
Block et al. teach stradomer units comprising IgG1 Fc domain and a multimerization domain (e.g. see [0014] in page 5). Block et al. teach that the multimerization domain is an IgG2 hinge region lined to the Fc domain (e.g. see [0023] in page 8).
Block et al. teach that the stradomer G045c (SEQ ID NO:4) exhibits increased binding to all Fc receptors including FcγRIIIa (e.g. see [00227] in page 77). Further, Block et al. teach that the homodimeric stradomer units can form higher orders, e.g. six homodimeric stradomer units via self-aggregation (e.g. see Figure 1h and [0064]-[0065]). Block et al. teach that the Fc domain can be mutated to improve the binding to FcγR (e.g. see pages 36-37).
Block’s SEQ ID NO:4 is 98.2% identical to instant SEQ ID NO:31 (see sequence alignment below)
RESULT 6
AZT01893
(NOTE: this sequence has 9 duplicates in the database searched)
ID AZT01893 standard; protein; 264 AA.
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AC AZT01893;
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DT 15-MAR-2012 (first entry)
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DE Inflammatory disease treatment related fusion protein G045c, SEQ ID 4.
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KW IgG1; IgG2; Immunoglobulin G1; Immunoglobulin G2; alzheimers disease;
KW anemia; antiallergic; antianemic; antiarthritic; antibacterial;
KW antidiabetic; antiinflammatory; antimicrobial-gen; antiparkinsonian;
KW antipsoriatic; arthritis; atopic dermatitis; autoimmune disease;
KW bacterial infection; celiac disease;
KW chronic inflammatory demyelinating polyneuropathy; dermatological;
KW endocrine-gen.; fusion protein; gastrointestinal-gen.;
KW genetic-disease-gen.; hashimotos disease; hematological-gen.;
KW huntingtons chorea; idiopathic thrombocytopenic purpura;
KW immune modulation; immunomodulator; immunosuppressive;
KW infectious disease; inflammatory bowel disease; inflammatory disease;
KW insulin dependent diabetes; kawasaki disease; metabolic-gen.;
KW multiple sclerosis; musculoskeletal-gen.; myasthenia gravis;
KW neuroprotective; nootropic; osteopathic; osteopenia; osteoporosis;
KW parkinsons disease; protein production; protein therapy; psoriasis;
KW recombinant protein; scleroderma; systemic lupus erythematosus;
KW therapeutic; uveitis; vasotropic; viral infection; virucide.
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OS Homo sapiens.
OS Synthetic.
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FH Key Location/Qualifiers
FT Peptide 1..20
FT /label= Signal_peptide
FT Domain 21..252
FT /label= Immunoglobulin_G1_Fc_domain
FT Domain 253..264
FT /label= Immunoglobulin_G2_multimerization_domain
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CC PN WO2012016073-A2.
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CC PD 02-FEB-2012.
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CC PF 28-JUL-2011; 2011WO-US045768.
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PR 28-JUL-2010; 2010US-0368465P.
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CC PA (GLIK-) GLIKNIK INC.
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CC PI Block DS, Olsen H;
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DR WPI; 2012-B54767/12.
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CC PT New stradomer unit useful for treating e.g. arthritis, and type I
CC PT diabetes comprises leader sequence, immunoglobulin G1 crystalline
CC PT fragment domain, and multimerization domain, where leader sequence is
CC PT directly linked to the domain.
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CC PS Claim 20; SEQ ID NO 4; 124pp; English.
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CC The present invention relates to a novel stradomer unit comprising a
CC leader sequence, an immunoglobulin G1 (IgG1) crystalline fragment (Fc)
CC domain and a multimerization domain, where the leader sequence is
CC directly linked to the IgG1 Fc domain, and the IgG1 Fc domain is directly
CC linked to the multimerization domain or the leader sequence is directly
CC linked to the multimerization domain and the multimerization domain is
CC directly linked to the IgG1 Fc domain. The invention also provides: a
CC stradomer composition comprising the stradomer units; a cluster stradomer
CC comprising the stradomer units; a method for modulating an immune
CC response in a subject; a method for treating inflammatory disease in a
CC subject; a method for blocking nonspecific binding of antibodies in an in
CC vitro or ex vivo assay; a method for reducing endotoxin levels in a
CC composition; and a method for producing a cluster stradomer. The
CC stradomer composition is useful for treating inflammatory disease in a
CC subject, where the inflammatory disease is an autoimmune disease selected
CC from arthritis, multiple sclerosis, type I diabetes, autoimmune
CC thyroiditis, idiopathic thrombocytopenic purpura, chronic inflammatory
CC demyelinating polyneuropathy, scleroderma, autoimmune uveitis, systemic
CC lupus erythematous, myasthenia gravis, atopic dermatitis, autoimmune
CC anemia, psoriasis, inflammatory bowel disease, celiac disease, Kawasaki
CC Disease, sickle cell crisis. It is also useful for treating Alzheimer's
CC disease, Parkinson's disease, Huntingdon's disease, osteopenia, and
CC osteoporosis. The inflammatory disease is an infectious disease such as
CC bacterial infection, or viral infection. The present sequence represents
CC an inflammatory disease treatment related fusion protein comprising a
CC leader sequence, an IgG1 Fc domain, and an IgG2 multimerization domain
CC used in the stradomer composition of the invention.
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SQ Sequence 264 AA;
Query Match 98.2%; Score 1429; Length 264;
Best Local Similarity 98.5%;
Matches 260; Conservative 0; Mismatches 4; Indels 0; Gaps 0;
Qy 1 METDTLLLWVLLLWVPGSTGEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 METDTLLLWVLLLWVPGSTGEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISR 60
Qy 61 TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSAYRVVSVLTVLHQDWLN 120
||||||||||||||||||||||||||||||||||||||||||| ||||||||||||||||
Db 61 TPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLN 120
Qy 121 GKEYKCKVSNKALPAPIEKTISKAKGQPRRPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 180
||||||||||||||||||||||||||||| ||||||||||||||||||||||||||||||
Db 121 GKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPS 180
Qy 181 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNH 240
|||||||||||||||||||||||||||||||||||||||||||||||||||||| |||||
Db 181 DIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNH 240
Qy 241 YTQKYLSLSPGKERKCCVECPPCP 264
|||| |||||||||||||||||||
Db 241 YTQKSLSLSPGKERKCCVECPPCP 264
Block’s IgG1 Fc is EEM polymorph since it has an amino acid D in position 356 and M at position 358. Block teaches that the stradomers, a biological active biomimetic molecule comprising a human IgG Fc and a single naturally occurring multimerization domain, is advantage in overcoming the limitations of IVIG (e.g. see [0012]).
The reference teachings differ from the instant invention by not describing amino acid substitution T299A, E345R, E430G, and S440Y.
Wittrup et al. (US 8,815,237) teach an antibody comprising amino acid substitution T299A wherein the antibody is aglycosylated but retain the binding to Fcγ receptors (e.g. see claim 17). Wittrup et al. further teach that the aglycosylatd antibody enables significantly less expensive microbial manufacture of therapeutic agent containing Fc region (e.g. see lines 23-29 in col. 4).
Reyes et al. teach stability-engineered Fc polypeptide by substituting the pre-existing amino acid residue T (threonine) at position 299 with A (alanine) (e.g. see [0019]). Reyes et al. teach that the stabilized Fc polypeptide has enhanced half-life and is dimeric (e.g. see [0043] and [0045]). Reyes et al. further teach IgG1 consisting T299A substitution exhibits reduced binding to C1q (e.g. see Fig. 9 and [0131]).
Diebolder et al. teach an Fc variant comprising amino acid substitutions E345R, E430G, and S440Y readily formed hexamers in solution and exhibits increased CDC relative to the parent unmutated Fc (e.g. see paragraph spanning pages 2-3).
It would thus be obvious to one of ordinary skill in the art at the time the instant invention was filed to combine the teachings of the references to produce a multimer comprising the stradomer unit with amino acid substitutions T299A, E345R, E430G, and S440Y for the stability and hexamer formation and increased binding to C1q.
An ordinary skill in the art would have been motivated to do so, and have a reasonable expectation of success, since Block teaches higher orders of stradomer can be mutated in the Fc region for improved binding to Fc receptor, and Wittrup et al. and Reyes et al. teach T299A substitution in the Fc region of human IgG1 improves stability but reduced binding to C1q. However, Diebolder et al. teach substitution E345R, E430G, and S440Y in the Fc region of human IgG1 can yield hexamer and improve binding to C1q. As such, an ordinary skill in the art would be able to modify the therapeutic stradomer units disclosed in Block et al. with known methods of amino acid substitutions in the Fc region to improve stability and improve binding to C1q or maintain C1Q binding as shown in Wittrup et al. and Reyes et al. and Diebolder et al.
Given that a compound cannot be separated from its properties, see In re Papesch, 315 F.2d 381,391 (CCPA 1963) (“a compound and all its properties are inseparable), the prior art compound having identical structures of the instantly claimed homodimeric stradomers (namely amino acid substitutions T299A, E345R, E430G, and S440Y) would inherently/intrinsically have the same properties as the instantly claimed homodimers including capable of multimerizing said homodimeric stradomer units, or exhibits retained or enhanced binding to FcγRI relative to a homodimeric stradomer of the same structure that does not comprise the T299A mutations as recited in instant claims 77-89.
Applicant’s arguments have been fully considered but have not been found persuasive.
Applicant argues that the reference cited by the Examiner teaches away from the instant invention because Reyes discloses T299A substitution in the Fc region exhibit reduced binding to C1q while the instant claims recite retained and thus one of skill seeking maintain or improved C1q binding in the art would not have incorporated T299A into the stradomer molecule.
Applicant further asserts that there is no reasonable expectation of success arriving at the claimed stradomers because it is unpredictable whether T299A or E345R, E430G and S440Y substitutions in monoclonal antibody would behave the same way in stradomers as set forth in [00119] in the instant specification which discloses that mutations effects of Fc binding affinity in monoclonal antibody may be different in stradomers.
Furthermore, applicant argues the recited stradomers has unexpected and superior properties in that even though T299A substitution reduced or eliminates binding to C1q in monoclonal antibodies, when incorporated into stradomer, T299A in G1098, G1126, and G1127 unexpectedly retained binding to C1q. The superior binding to canonical Fcγ receptors and complement proteins may be promoted by increased avidity in the hexameric complexes ash shown in Table 4.
As such, applicant asserts that the rejection should be withdrawn.
This is not found persuasive for following reasons:
In contrast to applicant’s arguments relying upon the unexpected and surprising results of the retained C1q binding, note the results of variant G1098 (T299A/E430G/S440Y), G1126 (T299S/E345R/E430G/S440Y), G1127 (T299A/E345R) as well as the control these variants are compared to in Table 4 in instant specification as-filed are note commensurate in scope of the instant claims.
Specifically, in Table 4 in page 80 of the instant specification, applicant discloses that stradomers G1098 (T299A/E430G/S440Y), G1126 (T299S/E345R/E430G/S440Y), G1127 (T299A/E345R) demonstrated retained binding to complement protein as measured by CDC inhibition relative to GL-2045 which appears to be the parent stradomer of G1098 (T299A/E430G/S440Y), G1126 (T299S/E345R/E430G/S440Y), G1127 (T299A/E345R).
The instant claims recite a homodimeric stradomer unit “demonstrates retained C1q binding relative to a homodimeric stradomer unit that does not comprise T299A and E345R, E430G and S440Y or E345R, E430G and S440Y. Thus, the instant claims allow the comparison of C1q binding to any other homodimeric stradomer unit so long as it does not have T299A and any mutations recited in (a), (b), or (c).
Therefore, the comparison disclosed in Table 4 in the instant specification regarding “retained C1q binding” relative to GL-2045” is not commensurate in scope with the instant claims.
Further, contrary to applicant assertion that the Wittrup et al. and Reyes et al. teach away from the instant invention by disclosing T299A reduced C1q binding, note that both Wittrup and Reyes teach the other benefit of T299A substitution in the Fc region--stabilizing the Fc region that is also aglycosylated.
For example, Reyes states:
“[0553] It is highly desirable for a protein therapeutic to have a long shelf life, with minimal changes to the physical or chemical properties of the protein during manufacturing production and storage. Evaluating related stresses is an important part of formulation development and two types of associated stress were evaluated for the IgG Fc mutants.”
Reyes teaches that T299 is a determinant stability, e.g. see Example 9 and claims 100-102).
Wittrup teaches amino acid substitution such as T299A eliminates glycosylation in the Fc region and can reduce cost in antibody production, however, aglycosylated antibody may not bind Fc receptor and C1q, key components of efficacy for anti-cancer antibodies (e.g. see cols. 2-3). Wittrup teaches that incorporation of amino acid substitutions in the Fc region can retain or exceed the ability of the corresponding wild type antibody to bind FcγRIIIA (e.g. see lines 22-39 in col. 2).
Therefore, while T299A substitution can eliminate the binding to C1q, its benefit of producing an antibody with stability in the Fc region and longer shelf life would have motivated an ordinary skill in the art to incorporated the T299A into the stradomer in order to produce a stable product.
While T299A eliminates Fc’s binding to C1q, such deficiency can be compensated by incorporate additional amino acid substitutions that enhanced binding to C1q such as E345R as taught by Diebolder et al. which explicitly teach E345R substitution increased C1q avidity to opsonized cell by a factor of 5 and complement dependent cytotoxicity (CDC) by a factor of 10 when introduced to IgG1 antibody and thus can be used to overcome mutations that would inhibit CDC (e.g. see right col. in page 1260). Diebolder et al. further E345R combined with two additional enhancing mutations E430G and S440Y promotes hexamer formation and also showed stronger CDC relative to single mutation (e.g. see Fig. 2E).
Therefore, an ordinary skill in the art would have been motivated to combine the teachings of the references to introduce T299A and E345R, E430G, and S440Y into the Fc region of stradomers following routine and well-established methods of introducing mutations into the stradomers as disclosed by Block. Given that it was known in the art that T299A is beneficial in stabilize the Fc region and prolong shelf-life and given that the triple mutations E354R, E430G, and S440Y were known to enhance CDC and promote hexamer formation, an ordinary skill in the art would have been able to combine the mutations in the Fc region of human IgG for forming stradomers with a reasonable expectation of success. The combination of the mutations would overcome the inhibition of C1q binding as a result of T299A substitution while taking advantage of its ability to stabilize Fc region in view of the teachings of Diebolder et al. (E345R substitution overcome the inhibition of CDC by S440Y, see right col. in page 1260).
Further, Block teaches that very minor changes to the polypeptide of stradomers may also create a stradomer capable of enhanced or decreased binding of Fc binding to multiple Fcγ receptors (e.g. see [0094]), and routine experimentations based on extensive mutagenesis studies from human IgG Fc region and its receptors were known (e.g. see [0092]).
As such, combining well known amino acid substitutions T299A disclosed by Wittrup and Reyes with the triple mutations E345R, E430G, and S440Y when making stradomers disclosed by Block to create a stradomer variant with stabilized Fc region, prolonged shelf life would be well within the skill of an ordinary artisan.
Given that it was also known that the triple mutations E345R, E430G, and S440Y promote hexamer formation and enhance CDC activity, it would be expected that combining the triple mutations with T299A would overcome the lack of complement binding and activation induced by T299A.
As such, applicant’s arguments have not been found persuasive.
7. No claim is allowed.
8. THIS ACTION IS MADE FINAL. 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.
9. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHUN DAHLE whose telephone number is (571)272-8142. The examiner can normally be reached Mon-Fri 6:30am-4:00pm.
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, Misook Yu can be reached at 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHUN W DAHLE/Primary Examiner, Art Unit 1641
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