Office Action 1: Non-Final Rejection (2024-09-12)
Rejection types: 103 - Obviousness, 112 - Written Description/Enablement, Double Patenting

CLAIMS:
CLAIMS

1\. A method for determining the effective dose of a multi-Fc therapeutic comprising:
(a) administering the multi-Fc therapeutic to a subject in need thereof at a starting dose for said multi-Fc therapeutic;
(b) measuring the level of circulating iC3b in the subject;
(c) determining that the subject requires a first cumulative escalated dose of the multi-Fc therapeutic if the patient has been determined to have:
(i) blood levels of iC3b lower than a predetermined threshold following administration with the starting dose of the multi-Fc therapeutic; or
(ii) blood levels of iC3b with a change percent of less than about 10%, less than about 20%, less than about 30%, less than about 40% or less than about 50% from baseline;
and (d) administering a first cumulative escalated dose of the multi-Fc therapeutic, wherein the multi-Fc therapeutic comprises a multimer of a homodimer and wherein the homodimer comprises a monomer comprising amino acids 21-264 of SEQ ID NO:4.

2\. The method of claim 1, further comprising:
(e) repeating the determination of a blood iC3b level of the patient after administration of the first cumulative escalated dose of the multi-Fc therapeutic; and
(f) administering a second cumulative escalated dose of the multi-Fc therapeutic that is higher than the previously administered cumulative escalated dose if the patient is determined to have:
(i) blood levels of iC3b lower than a predetermined threshold following administration with the starting dose of the multi-Fc therapeutic; or
(ii) blood levels of iC3b with a change percent of less than about 10%, less than about 20%, less than about 30%, less than about 40% or less than about 50% from baseline.

3\. The method of claim 1, wherein the repeated determination of blood iC3b levels is repeated with continued cumulative doses of the multi-Fc therapeutic until the predetermined iC3b threshold is met, or until the levels of iC3b have changed by greater than about 10%.

4\. The method of claim 1, wherein the first cumulative escalated dose of the multi-Fc therapeutic is least about 105% of the starting dose of said multi-Fc therapeutic.

5\. The method claim 1, wherein administering a cumulative escalated dose comprises administering an escalated dose of the multi-Fc therapeutic throughout the dosing period.

6\. The method of claim 1, wherein administering a cumulative escalated dose comprises administering both an escalated dose and an incremental dose during the dosing period.

7\. The method of claim 1, wherein the cumulative escalated dose of the multi-Fc therapeutic is at least about 110%, about 115%, about 120%, about 125%, about 150%, about 175%, or about 200% of the previously administered dose of said multi-Fc therapeutic.

8\. The method of claim 1, wherein the predetermined threshold of iC3b is about 25 pg/mL to about 300 pg/mL, about 50 pg/mL to about 200 pg/mL, about 75 pg/mL to about 125 pg/mL, or
about 100 pg/mL.

9\. The method of claim 1, wherein the predetermined threshold of iC3b is about 25% of neutrophils and monocytes that are iC3b+.

10\. The method of claim 1, wherein the predetermined threshold of iC3b is an iC3b mean fluorescence intensity (MFI) of about 125% of the baseline iC3b MFI.

11\. The method of claim 1, wherein the percent change is less than about 20%, less than about 30%, less than about 40% or less than about 50%.

12\. The method of claim 1, wherein the iC3b level is determined by measurement of a surrogate marker for iC3b.

13\. The method of claim 12, wherein the surrogate marker for iC3b is selected from the group consisting of iC3bl, iC3b2, C3a, C3a desArg, C4a, C4a desArg, C3f, C3dg, C3d, C3g and a combination thereof.

14\. The method of claim 12, wherein the surrogate marker for iC3b is C3a or C4a.

15\. The method claim 12, wherein the predetermined threshold for the surrogate marker of iC3b is less than about 30 ng/mL, less than about 20 ng/mL, less than about 10 ng/mL or less than about 5 ng/mL.

16\. The method of claim 1, wherein the percent change of the surrogate marker is less than about 10%, less than about 20%, less than about 30%, less than about 40% or less than about 50%.

17\. The method of claim 1, wherein the autoimmune or inflammatory disease is selected from a group consisting of autoimmune cytopenia, idiopathic thrombocytopenic purpura (ITP), rheumatoid arthritis, systemic lupus erythematosus, asthma, Kawasaki disease, Guillain-Barre syndrome, Stevens-Johnson syndrome, Crohn's colitis, diabetes, chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis, anti-Factor VIII autoimmune disease, dermatomyositis, vasculitis, uveitis, and Alzheimer's disease.

18\. The method of claim 1, wherein the iC3b level is determined by an immunoassay.

19\. The method of claim 18, wherein the immunoassay comprises an ELISA or a western blot.

20\. The method of claim 1, wherein the iC3b level is determined by flow cytometry. 47 48 49

OFFICE 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 .
DETAILED ACTION
2.	Claims 1-20 are pending and currently under prosecution.
Priority
3.	Applicant’s claim under 35 U.S.C. §§ 119(e), 121 and 365(c) for benefit of the earlier filing date of application, is acknowledged.
Claim Rejections - 35 USC § 112
4.	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.
5.	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.
6.	Claims 1-4, 7-11 and 15-16 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 pre-AIA  the applicant regards as the invention.
Claims 1-4, 7-11 and 15-16 are indefinite because the claims recite “about”.
M.P.E.P. § 2173.05(b) III. A. states:
In determining the range encompassed by the term about, one must consider the context of the term as it is used in the specification and claims of the application. Ortho-McNeil Pharm., Inc. v. Caraco Pharm. Labs., Ltd., 476 F.3d 1321, 1326, 81 USPQ2d 1427, 1432 (Fed. Cir. 2007). InW.L. Gore & Associates, Inc. v. Garlock, Inc., 721 F.2d 1540, 220 USPQ 303 (Fed. Cir. 1983), the court held that a limitation defining the stretch rate of a plastic as exceeding about 10% per second is definite because infringement could clearly be assessed through the use of a stopwatch. However, in another case, the court held that claims reciting at least about were invalid for indefiniteness where there was close prior art and there was nothing in the specification, prosecution history, or the prior art to provide any indication as to what range of specific activity is covered by the term about. Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991).
In this case, there is nothing in the specification to provide any indication as to what range of specific activity is covered by the term about.
7.	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.
Claim Rejections - 35 USC § 103
8.	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 of this title, 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.
9.	The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
10.	Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Block et al. (WO 2012016073, published on 2 February 2012, IDS) in view of Olson et al. (US 20120315266, published on December 13, 2012, IDS).
Claims 1-20 are herein drawn to a method for determining the effective dose of a multi-Fc therapeutic comprising: (a) administering the multi-Fc therapeutic to a subject in need thereof at a starting dose for said multi-Fc therapeutic; (b) measuring the level of circulating iC3b in the subject; (c) determining that the subject requires a first cumulative escalated dose of the multi-Fc therapeutic if the patient has been determined to have: (i) blood levels of iC3b lower than a predetermined threshold following administration with the starting dose of the multi-Fc therapeutic; or (ii) blood levels of iC3b with a change percent of less than about 10%, less than about 20%, less than about 30%, less than about 40% or less than about 50% from baseline; and (d) administering a first cumulative escalated dose of the multi-Fc therapeutic, wherein the multi-Fc therapeutic comprises a multimer of a homodimer and wherein the homodimer comprises a monomer comprising amino acids 21-264 of SEQ ID NO:4.
Block et al. teach a method of treating an inflammatory or autoimmune disease in a subject in need thereof comprising administering an effective amount of a stradomer comprising at least two stradomer units each comprising a leader sequence directly linked to an IgG 1 Fc domain which in turn is directly linked to a multimerization domain or alternatively comprising a leader sequence directly linked to a multimerization domain which in turn is directly linked to a an IgG 1 Fc domain, wherein the subject includes human; see entire document, e.g. [0038], [0043], claims 36-39, 31 and 1. The stradomer of Block et al. comprises multi-Fc; see Fig. 1. Block et al. teach an effective dosage of the multi-Fc; see pages 12-15. Block et al. teach autoimmune disease includes Alzheimer's disease; see [0038].
Block et al. teach the stradomer unit comprises SEQ ID NO: 4; see claim 20, [0019]. SEQ ID NO: 4 of Block et al. is 100% identical with the instant claimed SEQ ID NO: 4; see sequence alignments below.
Block et al. do not teach determining the level of iC3b.
However, this deficiency is remedied by Olson et al.
Olson et al. teach a method of detecting a level of iC3b in a sample from a patient with autoimmune disease, and administering treatment to treat the patient if the detected level is below the reference level; see entire document, e.g., claim 1, [0008-0009]. Olson et al. teach the treatment encompasses modifying a treatment the individual has already received or is receiving; [00871].
Olson et al. teach the iC3b level is determined by ELISA; see Example 7.
Olson et al. teach the iC3b level is determined by flow immunoassay; see [0010].
Olson et al. teach C3a and C4a; see [0088-0099].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references so as to modify the teachings of Olson et al. to provide an autoimmune disease patient determined to have an inadequate response to a therapeutic (e.g., multi-Fc therapeutic) wherein the patient has been determined to have: blood levels of iC3b lower than a predetermined threshold following administration with the starting dose, as taught by Olson et al., in order to provide a determination that the detected level is below the reference level indicating that the subject is suffering from or susceptible to undesirable and/or pathologic complement activation, and administering treatment if the detected level is below the reference level; see [00161] of Olson et al.
Double Patenting
11.	The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees.  A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used.  Please visit http://www.uspto.gov/forms/.  The filing date of the application will determine what form should be used.  A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission.  For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
12.	Claims 1-20 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 157-171 of copending Application No. 17/400367 in view of Olson et al. (US 20120315266, published on December 13, 2012, IDS).
Claims 1-20 are herein drawn to a method for determining the effective dose of a multi-Fc therapeutic comprising: (a) administering the multi-Fc therapeutic to a subject in need thereof at a starting dose for said multi-Fc therapeutic; (b) measuring the level of circulating iC3b in the subject; (c) determining that the subject requires a first cumulative escalated dose of the multi-Fc therapeutic if the patient has been determined to have: (i) blood levels of iC3b lower than a predetermined threshold following administration with the starting dose of the multi-Fc therapeutic; or (ii) blood levels of iC3b with a change percent of less than about 10%, less than about 20%, less than about 30%, less than about 40% or less than about 50% from baseline; and (d) administering a first cumulative escalated dose of the multi-Fc therapeutic, wherein the multi-Fc therapeutic comprises a multimer of a homodimer and wherein the homodimer comprises a monomer comprising amino acids 21-264 of SEQ ID NO:4.
Claims 157-171 of copending Application No. 17/400367 are drawn to a method of treating autoimmune disease in a subject in need thereof comprising administering an effective amount of a cluster stradomer, wherein a stradomer unit comprising: (a) a leader sequence(b) an IgG1 Fc domain; and (c) a multimerization domain; wherein the leader sequence is directly linked to the IgG1 Fc domain and wherein the IgG1 Fc domain is directly linked to the multimerization domain or wherein the leader sequence is directly linked to the multimerization domain and the multimerization domain is directly linked to the IgG1 Fc.
Claims of copending Application No. 17/400367 do not teach determining the level of iC3b.
However, this deficiency is remedied by Olson et al.
Olson et al. teach a method of detecting a level of iC3b in a sample from a patient with autoimmune disease, and administering treatment to treat the patient if the detected level is below the reference level; see entire document, e.g., claim 1, [0008-0009]. Olson et al. teach the treatment encompasses modifying a treatment the individual has already received or is receiving; [00871].
Olson et al. teach the iC3b level is determined by ELISA; see Example 7.
Olson et al. teach the iC3b level is determined by flow immunoassay; see [0010].
Olson et al. teach C3a and C4a; see [0088-0099].
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references so as to modify the teachings of Olson et al. to provide an autoimmune disease patient determined to have an inadequate response to a therapeutic (e.g., multi-Fc therapeutic) wherein the patient has been determined to have: blood levels of iC3b lower than a predetermined threshold following administration with the starting dose, as taught by Olson et al., in order to provide a determination that the detected level is below the reference level indicating that the subject is suffering from or susceptible to undesirable and/or pathologic complement activation, and administering treatment if the detected level is below the reference level; see [00161] of Olson et al.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
13.	No claim is allowed.
14.

APPLICANT REBUTTAL: REMARKS
Upon entry of these amendments, claims 1-20 are pending in the present application. In this response, claims 1-5, 7-12, 15-18, and 20 have been amended to improve clarity. Support for the claim amendments can be found throughout the application as originally filed. No new matter is added. Entry and consideration are respectfully requested.
Amendment and cancellation of certain claims is not to be construed as a dedication to the public of any of the subject matter of the claims as previously presented.
Claim Rejections - 35 U.S.C.  S112
Claims 1-4, 7-11 and 15-16 stand rejected under 35 U.S.C. §112(b) or 35 U.S.C. §112 (pre- AIA), second paragraph, as allegedly being indefinite for reciting the term "about." Office Action, pages 2-3.
Without acquiescing to the propriety of the rejection and solely in an effort to expedite prosecution, claims 1-4, 7-11 and 15-16 have been amended to remove the term "about", thus rendering this rejection moot.
Claim Rejections - 35 U.S.C.  S103
Claims 1-20 stand rejected under 35 U.S.C. §103 as being unpatentable over Block et al. (WO 2012016073, published on February 2, 2012, ("Block")) in view of Olson et al. (U.S. Publication No. 2012-03 15266, published on December 13, 2012, ("Olsen")). Office Action, pages 3-5.
The present claims are directed to a method for determining an effective dose of a multi- Fc therapeutic comprising: (a) administering the multi-Fc therapeutic to a subject in need thereof at a starting dose of the multi-Fc therapeutic; (b) determining the blood iC3b level of the subject;
(c) determining that the subject requires a first cumulative escalated dose of the multi-Fc therapeutic if the subject has been determined to have: (i) a blood iC3b level lower than a
predetermined threshold following administration with the starting dose of the multi-Fc therapeutic; or (ii) a blood iC3b level with a change percent of less than 10%, less than 20%, less than 30%, less than 40%, or less than 50% from baseline; and (d) administering a first cumulative escalated dose of the multi-Fc therapeutic, wherein the multi-Fc therapeutic comprises multimers of a homodimer and wherein the homodimer comprises a monomer comprising amino acids 21- 264 of SEQ ID NO:4. By utilizing blood iC3b levels as a marker, the present method enables the determination of the maximally effective dose of the multi-Fc therapeutic with the minimum amount of the therapeutic, thereby reducing adverse effects of overdosing and minimizing therapeutic waste. See paragraph [0009] of the present application.
Neither Block nor Olson teaches or suggests utilizing iC3b as a marker to determine the maximally effective dose of the multi-Fc therapeutic. Block teaches multimerizing stradomers, including homodimeric stradomer units comprising monomers of SEQ ID NO: 4. However, Block fails to teach strategies for determining the maximally effective dose of the multi-Fc therapeutic and is completely silent on the relevance of iC3b for such methods.
Olson is directed generally to methods of detecting iC3b. See e.g., paragraph [0008] of Olson. There is nothing in Olson that provides any teaching or suggestion that iC3b levels can be used to determine the appropriate dose of the multi-Fc therapeutic. Olson describes detection of iC3b and subsequent modification of a subject's treatment regimen to
decrease
pathologic complement activation. See paragraph [0131] of Olson, which states "Accordingly, the clinician may then modify the individual's treatment by increasing the dosage of medications, such as anti- inflammatory agents or complement inhibitors, until a desired
stabilization or decrease in complement activation
levels is achieved." See also Olson at paragraph [0117], which describes determining a level of iC3b in a subject, wherein a detection level above a threshold of iC3b indicates that the subject is suffering from or susceptible to
undesirable and/or patholo
gic
complement activation.
See also paragraph [0112] of Olson which states that the concentration of iC3b correlates to a severity of inflammatory distress. Treatment is then administered to
decrease
the undesired complement activation. This is directly counter to the teachings of the present application.
In particular, paragraph [0043] of the present application states that, in contrast to the teachings of Olson, the data provided in the present application indicates that higher levels of iC3b are
desirable
in the treatment of autoimmune and inflammatory disorders. Therefore, the present methods generally utilize iC3b to determine that a sufficient level of
complement activation
has occurred in order to achieve a desired therapeutic effect. See paragraphs [0039] and [0043] of the present application. Increasing doses of the multi-Fc therapeutic are administered until a sufficient
increase
in iC3b levels has occurred to indicate that the subject is responsive to the multi-Fc therapeutic. Olson describes the exact opposite - i.e., adjusting medication until a
decrease
in complement activation is achieved. See paragraph [0117] of Olson.
For at least the foregoing reasons, Applicant submits that the present claims are not obvious over Block in view of Olson and respectfully requests withdrawal of this rejection under 35 U.S.C. § 103.
Double Patenting
Claims 1-20 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as allegedly being unpatentable over claims 157-171 of copending Application No. 17/400,367 (now issued as US patent 12,084,482) ("the '367 application") in view of Olson. Office Action, pages 5-7.
A nonstatutory double patenting rejection made under the obviousness analysis should make clear "the reasons why a person of ordinary skill in the art would conclude that the invention defined in the claim at issue would have been an obvious variation of the invention defined in a claim in the patent." MPEP 804(II)(B)(3). The '367 application is a divisional application of the US national phase of Block. As discussed above, neither Block nor Olson teaches or suggests utilizing iC3b as a marker to determine the maximally effective dose of the multi-Fc therapeutic as presently claimed.
As a first point, and as the Examiner admits, the '367 application "do[es] not teach determining the level of iC3b." Office Action, page 7.
Secondly, and as discussed above, Olson fails to teach or suggest that iC3b levels can be used to determine the appropriate dose of the multi-Fc therapeutic. In fact, the teachings of Olson are counter to that of the present application. Olson teaches iC3b measurements as an indicative of
patholo
g
ic complement activation
and modification of a subject's treatment in order to
decrease
said complement activation. In contrast, the present application teaches iC3b measurements as indicative of
desirable complement activation
and increasing of a treatment dose of the multi-Fc therapeutic until a sufficient
increase
in iC3b levels and complement activation has occurred.
For at least the foregoing reasons, Applicant submits that the combination of the '367 application and Olson is not appropriate for a nonstatutory double patenting rejection. Applicant therefore respectfully requests withdrawal of this rejection.
CONCLUSION

NEXT OFFICE 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 .
EXAMINER'S COMMENT
2.	The amendment/argument filed 12/10/2024, has been entered.
Any comments considered necessary by applicant must be submitted no later than the payment of the Issue Fee and, to avoid processing delays, should preferably accompany the Issue Fee. Such submissions should be clearly labeled Comments on Statement of Reasons for Allowance.
Conclusion
4.	Claims 1-20 have been allowed.
5.

CITED REFERENCE SUMMARIES: Ref US20120315266: Claims:
1. A method comprising steps of
detecting in a sample from a subject a level of intact C3, wherein the detecting involves specific interaction between the intact C3 and a non-cross-reactive antibody thereto; comparing the detected level with a reference level, which reference level is within a range of about 350 ug/ml to about 1,700 ug/ml; wherein determination that the detected level is below the reference level indicates that the subject is suffering from or susceptible to undesirable and/or pathologic complement activation; and administering treatment to treat undesired complement activation if the detected level is below the reference level.
2. The method of claim 1, wherein the non-cross-reactive antibody is characterized in that a 1 ug/ul solution of iC3b produces a signal equivalent to less than about 1 ng/ml of C3.
3. The method of claim 2, wherein the non-cross-reactive antibody is or comprises HM2075.
4. The method of claim 1, wherein the detecting and comparing steps may be carried out in about 30 minutes or less.
5. The method of claim 1, wherein the undesirable and/or pathologic complement activation is caused by a disorder selected from the group consisting of systemic lupus erythematosus, trauma, inflammatory stress, autoimmune disorders, intracranial hemorrhage, infection, transplant rejection, ocular disease, heart disease, ischemia/reperfusion injury, age-related macular degeneration, paroxysmal nocturnal hemoglobinuria, hereditary angiodema, renal disease, pregnancy-associated disorders, and neurological disorders.
6. The method of claim 1, wherein the sample is selected from the group consisting of whole blood, serum, plasma, urine, tears, saliva, wound exudate, bronchioalveolar lavage fluid, and cerebrospinal fluid.
7. The method of claim 1, wherein the step of detecting is performed under controlled conditions such that performance of the step does not substantially activate complement within the sample.
8. The method of claim 1, wherein the detecting and comparing steps are not carried out using an ELISA assay.
9. The method of claim 1, wherein the detecting and comparing steps are carried out using a lateral flow assay.
10. A method comprising steps of
detecting in a sample from a subject a level of iC3b wherein the detecting involves specific interaction between the iC3b and a non-cross-reactive antibody thereto; comparing the detected level with a reference level, which reference level is within a range of about 10 ng/ml to about 5,000 ng/ml; wherein determination that the detected level is above the reference level indicates that the subject is suffering from or susceptible to undesirable and/or pathologic complement activation; and administering treatment to treat undesired complement activation if the detected level is above the reference level.
11. The method of claim 10, wherein the non-cross-reactive antibody is characterized in that a 1 ug/ul solution of C3 produces a signal equivalent to less than about 1 ng/ml of iC3b.
12. The method of claim 10, wherein the non-cross-reactive antibody is or comprises an antibody selected from the group consisting of A209, MCA2607, and HM2199.
13. The method of claim 10, wherein the detecting and comparing steps may be carried out in about 30 minutes or less.
14. The method of claim 10, wherein the undesirable and/or pathologic complement activation is caused by a disorder selected from the group consisting of systemic lupus erythematosus, trauma, inflammatory stress, autoimmune disorders, intracranial hemorrhage, infection, transplant rejection, ocular disease, heart disease, ischemia/reperfusion injury, age-related macular degeneration, paroxysmal nocturnal hemoglobinuria, hereditary angiodema, renal disease, pregnancy-associated disorders, and neurological disorders.
15. The method of claim 10, wherein the sample is selected from the group consisting of whole blood, serum, plasma, urine, tears, saliva, wound exudate, bronchioalveolar lavage fluid, and cerebrospinal fluid.
16. The method of claim 10, wherein the step of detecting is performed under controlled conditions such that performance of the step does not substantially activate complement within the sample.
17. The method of claim 10, wherein the detecting and comparing steps are not carried out using an ELISA assay
18. The method of claim 10, wherein the detecting and comparing steps are carried out using a lateral flow assay.
19. A method comprising the steps of
detecting in a sample a ratio of intact C3 level to iC3b level, wherein the detecting involves specific interaction between the intact C3, the iC3b, or both with a non-cross-reactive antibody thereto; comparing the detected level with a reference ratio of about 0.001 wherein determination that the detected level is below the reference level indicates that the subject is suffering from or susceptible to undesirable and/or pathologic complement activation; and administering treatment to treat undesired complement activation if the detected level is below the reference level.
20. The method of claim 19, wherein the detecting and comparing steps may be carried out in about 30 minutes or less.
21. The method of claim 19, wherein the non-cross-reactive antibody for detecting intact C3 is or comprises HM2075.
22. The method of claim 19, wherein the non-cross-reactive antibody for detecting iC3b is or comprises an antibody selected from the group consisting of A209, MCA2607, and HM2199.
23. The method of claim 19, wherein the undesirable and/or pathologic complement activation is caused by a disorder selected from the group consisting of systemic lupus erythematosus, trauma, inflammatory stress, autoimmune disorders, intracranial hemorrhage, infection, transplant rejection, ocular disease, heart disease, ischemia/reperfusion injury, age-related macular degeneration, paroxysmal nocturnal hemoglobinuria, hereditary angiodema, renal disease, pregnancy-associated disorders, and neurological disorders.
24. The method of claim 19, wherein the sample is selected from the group consisting of whole blood, serum, plasma, urine, tears, saliva, wound exudate, bronchioalveolar lavage fluid, and cerebrospinal fluid.
25. The method of any one of claims 19, wherein the step of detecting is performed under controlled conditions such that performance of the step does not substantially activate complement within the sample.
26. The method of claim 19, wherein the detecting and comparing steps are not carried out using an ELISA assay
27. The method of claim 19, wherein the detecting and comparing steps are carried out using a lateral flow assay.
Ref WO2012016073: Claims:
Claims: 1 . A stradomer unit comprising: (a) a leader sequence; (b) an IgG l Fc domain; and (c) a multimerization domain; wherein the leader sequence is directly linked to the IgG l Fc domain and wherein the IgG l Fc domain is directly linked to the multimerization domain or wherein the leader sequence is directly linked to the multimerization domain and the multimerization domain is directly linked to the IgG l Fc domain. 2. The stradomer unit of claim 1 wherein the amino acid sequence of the said IgG l Fc domain is at least 80% homologous to SEQ ID NO: 2. 3. The stradomer unit of claim 1 wherein the amino acid sequence of the said IgG l Fc domain is at least 90% homologous to SEQ ID NO: 2. 4. The stradomer unit of claim 1 wherein the amino acid sequence of the said IgG l Fc domain is at least 95% homologous to SEQ ID NO: 2. 5. The stradomer unit of claim 1 wherein the amino acid sequence of the said IgGl Fc domain is at least 99% homologous to SEQ ID NO: 2. 6. The stradomer unit of claim 1 wherein the multimerization domain is selected from the group consisting of an IgG2a hinge, an isoleucine zipper and a GPP domain and is capable of multimerizing said stradomer units. 7. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 80% homologous to SEQ ID NO: 3 and is capable of multimerizing said stradomer units. 8. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 90% homologous to SEQ ID NO: 3 and is capable of multimerizing said stradomer units. 9. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 95% homologous to SEQ ID NO: 3 and is capable of multimerizing said st 10. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 99% homologous to SEQ ID NO: 3 and is capable of multimerizing said stradomer units. 1 1 . The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 80% homologous to SEQ ID NO: 3 and is capable of multimerizing said stradomer units. 12. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 90% homologous to SEQ ID NO: 5 and is capable of multimerizing said stradomer units. 1 3. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 95% homologous to SEQ ID NO: 5 and is capable of multimerizing said stradomer units. 14. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 99% homologous to SEQ ID NO: 5 and is capable of multimerizing said stradomer units. 15. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 80% homologous to SEQ ID NO: 26 and is capable of multimerizing said stradomer units. 16. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 90% homologous to SEQ ID NO: 26 and is capable of multimerizing said stradomer units. 17. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 95% homologous to SEQ ID NO: 26 and is capable of multimerizing said stradomer units. 18. The stradomer unit of claim 6 wherein the amino acid sequence of the said multimerization domain is at least 99% homologous to SEQ ID NO: 26 and is capable of multimerizing said stradomer units. 1 9. The stradomer unit of claim 1 wherein the multimerization domain is directly linked to the carboxy terminus of the IgG l Fc domain. 20. The stradomer unit of claim 1 wherein the multimerization domain is directly linked to the amino terminus of the IgG l Fc domain. 20. The stradomer unit of claim 1 wherein the stradomer unit comprises SEQ ID NO: 4, SEQ ID NO:8, SEQ ID NO:9 SEQ ID NO: 10, SEQ ID NO: 27 or SEQ ID NO: 28. 22. The stradomer unit of claim 1 wherein the said multimerization domain creates multimers of said stradomer units. 23. The stradomer unit of claim 22 wherein the multimers of said stradomer units are high order multimers. 24. A stradomer composition comprising stradomer units of claim 23 wherein the mutlimers are present at a percentage of at least about 45% of the total stradomer composition. 25. A stradomer composition comprising stradomer units of claim 23 wherein the mutlimers are present at a percentage of at least about 55%> of the total stradomer composition 26. A stradomer composition comprising stradomer units of claim 23 wherein the mutlimers are present at a percentage of at least about 65% of the total stradomer composition 27. A stradomer composition comprising stradomer units of claim 23 wherein the mutlimers are present at a percentage of at least about 70% of the total stradomer composition 28. A stradomer composition comprising stradomer units of claim 23 wherein the mutlimers are present at a percentage of at least about 73% of the total stradomer composition 29. The stradomer unit of claim 1 wherein the IgG l Fc domain is capable of binding FcRn, DC- SIGN, SIGN-R1 or an FcyR. 30. The stradomer unit of claim 1 wherein the FcyR is FcyRIIIa. 3 1 . A cluster stradomer comprising at least two stradomer units of claim 1 . 32. The cluster stradomer of claim 3 1 , wherein said stradomer binds to FcyRII Ia. 33. A method of modulating an immune response in a subject comprising administering to the subject an effective amount of a cluster stradomer of claim 31 . 34. The method of claim 33 wherein said modulation comprises induction of CD86 on dendritic cells. 35. The method of claim 33 wherein said modulation comprises inhibition of CD l a expression on dendritic cells. 36. A method of treating inflammatory disease in a subject in need thereof comprising administering an effective amount of a cluster stradomer of claim 31. 37. The method of claim 36 wherein the inflammatory disease is an autoimmune disease. 38. The method of claim 37 wherein the autoimmune disease is selected from the group consisting of arthritis, multiple sclerosis, type I diabetes, autoimmune thyroiditis, idiopathic thrombocytopenic purpura, chronic inflammatory polyneuropathy, scleroderma, autoimmune uveitis, systemic lupus erythematosus, myasthenia gravis, and atopic dermatitis. 39. The method of claim 37 wherein the autoimmune disease is associated with the transplantation of an organ form a donor to a recipient. 40. The method of claim 36 wherein the inflammatory disease is an infectious disease. 41 . The method of claim 36 wherein the infectious disease is a bacterial infection. 42. The method of claim 36 wherein the infectious disease is a viral infection. 43. The method of claim 36 wherein said cluster stradomer is administered intravenously, subcutaneously, orally, intraperitoneally, sublingually, buccally, transdermal ly, by subdermal implant, or intramuscularly. 44. The method of claim 36 wherein said cluster stradomer is administered intravenously. 45. The method of claim 36 wherein said cluster stradomer is administered at a dose of about 0.1 mg/kg to about 1000 mg/kg. 46. The method of claim 36 wherein the cluster stradomer is administered at a dose of about 1 mg/kg to about 25 mg/kg. 47. A method for blocking nonspecific binding of antibodies in an in vitro or ex vivo assay comprising incubating target tissue or target cells with a composition comprising an effective amountof the cluster stradomer of claim 31 . 48. The method of claim 47 wherein the antibodies are monoclonal antibodies. 49. The method of claim 47 wherein the antibodies are polyclonal antibodies. 50. The method of claim 47 wherein the in vitro or ex vivo assay is immunohistochemistry, flow cytometry, western blot, or an immunofluorescent assay. 51 . A method for reducing endotoxin levels in a composition comprising treating the composition with an effective amount of the cluster stradomer of claim 3 1 . 52. The method of claim 51 wherein the cluster stradomer complexes with the said endotoxin in the composition. 53. The method of claim 5 1 further comprising removing the stradomer complexed endotoxin from the composition. 54. The method of claim 53 wherein the stradomer complexed endotoxin is removed from the composition by filtration. 55. The method of claim 53 wherein the composition is a pharmaceutical composition. 56. A method for producing a cluster stradomer comprising expressing a sequence selected from the group consisting of SEQ ID NO: 4, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 8, SEQ ID NO: 20, SEQ ID NO: 21 , SEQ ID NO: 28, SEQ ID NO: 24, SEQ ID and NO: 27 in a host. 57. The method of claim 56 further comprising (cloning a DNAencoding the stradomer selected from the group consisting of SEQ ID NO:4, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO: 10 SEQ ID NO: 1 8, SEQ ID NO: 20, SEQ ID NO: 2 1 , SEQ ID NO: 28, SEQ ID NO: 24, SEQ ID and NO: 27 into an expression vector (b) transfecting the expression vector into a bacterial host; (c) isolating the plasmid DNA containing cloned DNA from the bacterial culture; (d) linearizing the plasmid DNA containing cloned DNA; (e) transfecting the linearized DNA into mammalian cells; (f) expanding the positively transfected cells to obtain a pool of stably transfected cells; (g) harvesting the stradomer protein from the media; (h) purifying the stradomer protein, wherein the stradomer protein contains no extraneous sequences. 58. The method of claim 57 wherein the expression vector contains a selectable marker. 59. The method of claim 58 wherein the selectable marker is an antibiotic resistance gene. 60. The method of claim 59 wherein the antibiotic resistance gene is a neomycin resistance gene. 61. The method of claim 57 wherein the mammalian cells are CHO cells or HE 293 cells. 62. The method of claim 57 wherein the stradomer protein is purified by affinity chromatography. 63. The method of claim 62 further purifying the stradomer by ion-exchange chromatography. 64. The method of claim 36 further comprising administering an additional pharmaceutically active agent. 65. The method of claim 64 wherein the additional pharmaceutically active agent comprises a steroid, a monoclonal antibody, an antibiotic, and anti-viral agent, a cytokine, or an agent otherwise capable of acting as an immune-modulator. 66. The method of claim 65 wherein the steroid is prednisolone, cortisone, mometesone testosterone, estrogen, oxandrolone, fluticasone, budesonide, beclamethasone, albuterol, or levalbuterol. 67. The method of any one of claims 64-66 wherein the additional pharmaceutically active agent and the cluster stradomer display therapeutic synergy. 68. The stradomer unit of claim 1 wherein the IgGl Fc domain lacks the IgG l hinge domain. 69. The stradomer unit of claim 1 , wherein the IgGl Fc consists of the IgG l CH2 and IgGl CH3 domains of SEQ ID NO: 19. 70. A stradomer unit comprising: (a) a leader sequence; and (b) an Fc domain comprising (1 ) the IgG2 hinge domain of SEQ ID NO: 3; and (2) the CH2 and CH3 domains of IgGl of SEQ ID NO: 19 71 . The stradomer unit of claim 70 wherein the IgG2 hinge domain creates multimers of said stradomer units. 72. The stradomer unit of claim 70 wherein the stradomer unit is at least 80% homologous to SEQ ID NO: 1 8. 73. The stradomer unit of claim 70 wherein the stradomer unit is at least 90% homologous to SEQ ID NO: 18. 74. The stradomer unit of claim 70 wherein the stradomer unit is at least 95% homologous to SEQ ID NO: 1 8. 75. The stradomer unit of claim 70 wherein the stradomer unit' is at least 99% homologous to SEQ ID NO: 18. 76. The stradomer unit of claim 69 wherein the IgG l Fc domain is capable of binding FcRn, DC-SIGN, SIGN-R1 or an FcyR. 77. The stradomer unit of claim 76 wherein the FcyR is FcyRIIIa. 78 . A cluster stradomer comprising at least two stradomer units of claim 70. 79. The cluster stradomer of claim 78, wherein said stradomer binds to FcyRIIIa. 80. A method of modulating an immune response in a subject comprising administering to the subject an effective amount of a cluster stradomer of claim 78. 81 . The method of claim 80 wherein said modulation comprises induction of CD86 on dendritic cells. 82. The method of claim 80 wherein said modulation comprises inhibition of CD l a expression on dendritic cells. 83. A method of treating inflammatory disease in a subject in need thereof comprising administering an effective amount of a cluster stradomer of claim 3 1 . 84. The method of claim 83 wherein the inflammatory disease is an autoimmune disease. 85. The method of claim 84 wherein the autoimmune disease is selected from the group consisting of arthritis, multiple sclerosis, type 1 diabetes, autoimmune thyroiditis, idiopathic thrombocytopenic purpura, chronic inflammatory polyneuropathy, scleroderma, autoimmune uveitis, systemic lupus erythematosus, myasthenia gravis, and atopic dermatitis. 86. The method of claim 84 wherein the autoimmune disease is associated with the transplantation of an organ form a donor to a recipient. 87. The method of claim 83 wherein the inflammatory disease is an infectious disease. 88. The method of claim 83 wherein the infectious disease is a bacterial infection. 89. T
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