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 .
Response to Amendment
Applicant’s remarks and amendments filed 7/21/2025, in response to the non-final rejection mailed 3/19/2025, are acknowledged and have been fully considered.
Any previous rejection or objection not mentioned herein is withdrawn.
Applicant’s amendment to the claims is acknowledged. This listing of the claims replaces all prior versions and listings of the claims. Claim 25 is withdrawn.
Claims 1-24 are pending and have been examined on the merits.
Claim Objections
Claim 2 is objected to because of the following informalities:
Claim 2 recites, in line 2, “the group consisting of heparinase, I, heparinase II, heparinase III.”. The conjunction “and” should appear before the last item in the list. Correction to: “the group consisting of heparinase, I, heparinase II, and heparinase III” is recommended.
Appropriate correction is required.
Claim Interpretation
As set forth previously, the phrase “detecting and/or quantitating FXIa in the sample by measuring activity of activated proteins” has been interpreted according to the B.R.I. in view of the specification to mean any which assay measures the FXIa activity of activating Factor IX (into FIXa) which in turns generates Factor Xa (FXa) from Factor X (FX) (see the description in the specification at [0057]). This encompasses direct enzyme measurements and other (e.g. in vivo) activity assays, under the B.R.I..
The specification at [0069] states: “As used herein, "FXIa activity assay" refer to any in vivo or in vitro assays to determine procoagulant activity, amidolytic activity or Factor XI zymogen. FXIa activity assays include thrombin generation assay (TGA), non-activated partial thromboplastin time (NAPTT) assay, FXIa determination with a Factor IX (FIX) based assay, in vivo wessler test, FXIa chromogenic assay, ELISA assay.”
Although limitations from the specification are not read into the claim, the specification herein is being used to determine the meaning of “measuring activity of activated proteins” and to determine the full intended scope of the claim.
CLAIM REJECTIONS
Claim Rejections - 35 USC § 103 (maintained)
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.
The factual inquiries 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.
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.
Claims 1-3 and 7-23 are rejected under 35 U.S.C. 103 as being unpatentable over “Wolberg” (2000. “Coagulation Factor XI is a Contaminant in Intravenous Immunoglobulin Preparations”. American Journal of Hematology 65:30-34) in view of Zimmermann et al. (US Pat. No. 5,262,325), Klein et al. (US PGPub No. 20070037236), and Hooper et al. (“Intravenous immunoglobulins: evolution of commercial IVIG preparations.” Immunol Allergy Clin North Am. 2008 Nov; 28(4):765-78).
Wolberg teaches that the zymogen Factor XI (FXI) and the activated version FXIa is present as a contaminant in some therapeutic intravenous immunoglobulin IgG (IVIG) preparations and contributes to the in vivo risk of thrombosis after IVIG therapy (Abstract; Figure 1). Wolberg teaches that XIa (activated factor XI) converts the zymogen Factor IX (FIX) to the activated Factor IX (FIXa) (page 33, under Discussion). Wolberg teaches methods of detecting the FXIa contamination in commercially available IVIG samples (see pg 31, Materials and “Assays for Activated Factor XI”; Figure 1).
For detecting and/or quantifying FXIa, Wolberg teaches an activity assay wherein Factor IX (20 nM final concentration) was incubated with IVIG samples, to allow any Factor XIa present to convert FIX to FIXa, and then Factor X (FX), poly-L-lysine, and a Chromozyme Th chromogenic substrate (300 nM, 30 nM, and 0.5 mM final concentrations, respectively) were added to determine the conversion rate of FIX to FIXa (pg 31, “Assays for Activated Factor XI”). Wolberg teaches that in this assay, FIXa, the product of FXI activity, converts FX to FXa, which is measured using the chromogenic substrate by monitoring continuously the absorbance at 405 nm in a plate-reading spectrophotometer (pg 31, “Assays for Activated Factor XI”).
However, Wolberg does not explicitly or inherently disclose the elimination of heparin from a plasma sample to be tested using heparinase.
Hooper et al. is a general review article cited to describe how commercial IVIG products are prepared. This is considered evidence regarding the general state of the knowledge, and the level of ordinary skill in the art. Hooper states that “All commercial IVIGs are produced from large pools of human plasma” (first line under “SECOND GENERATION INTRAVENOUS IMMUNOGLOBULIN” on page 766). Commercial products including plasma-derived IgG discussed in Hooper include all of those disclosed in Table 1. Thus, although Wolberg is overall silent regarding the plasma-based origin of the commercial IVIG products, one of skill in the art would have been aware that these comprise plasma-derived IgG.
Zimmerman discloses a heparinase formulation derived from Flavobacterium heparinum that can eliminate heparin interference of normal blood function (Abstract), and teaches that this heparinase is useful to eliminate the interference in hematological assays due to the presence of heparin (Abstract, Claim 1). Zimmerman discusses that the interference of heparin on coagulation assays is well-known in the art and that “[t]he most desirable resolution to the heparin interference problem would be a method that could expeditiously and specifically remove heparin from blood samples immediately before the onset of the test” (Col 2, lines 32- 65). Particularly, Zimmerman teaches that a suitably purified heparinase having specific heparin degradation activity against heparin would be desirable (Col 2, line 32- Col 3, line 26).
Zimmerman teaches an aPTT test, performed by determining the time required for a clot to form in a patient-derived plasma sample, which measures the aggregate activity of factors XII, XI, IX, VIII, X, II, V, and fibrinogen (Col 10, lines 1-20). Zimmerman teaches that the assay is commonly used as a coagulation screening test for factor dysfunction in hospitalized patients and states that a “method for determining heparin independent aPTT and PTT measurements would aid in the evaluation of these results” (Col 10, lines 18-47). In this embodiment (Example 4), Zimmerman teaches using 1.5 IU/mL heparinase to completely reverse the effects of up to 1.0 IU/mL heparin in citrated human plasma and Zimmerman teaches that a typical therapeutic heparin dose is 0.3 IU/mL (Table 6 and Col 10, lines 18-47).
Elsewhere (Example 3), Zimmerman teaches performing activated clotting time (ACT) assays, with and without heparin and/or heparinase (1.5 IU/mL) treatments (Col 9, Table 4). The results indicate that heparinase completely neutralized 6 IU/ml heparin and that the sample treated with both heparin and heparinase gave an identical result to a sample that had not been exposed to either reagent (Col 9, lines 1-21). Zimmerman also teaches that similar results are obtained over the range of 0-12 IU heparin/ml (Col 9, lines 10-11).
Regarding specific time-frames, Zimmerman states that “[t]he enzyme is allowed to dissolve into the sample and incubate for up to 60 minutes at 4°-37°C. In general, heparinase neutralization is complete within the time required for the enzyme to dissolve, less than 15 seconds. For example, 0.05 IU heparinase completely neutralizes the heparin in a 0.4 ml whole blood sample containing 4.8 IU heparin in 15 seconds. After incubation the sample is ready for processing by the intended hematological assay” (Col 6, lines 20-32).
Klein pertains to the diagnosis of blood coagulation and relates to a method for determining the heparin activity in a sample, where the sample is initially incubated with a heparin-modifying component (Abstract). Klein teaches that the heparin-modifying component includes the heparinase enzymes: heparinase I, heparinase II and heparinase III, which can be either directly obtained from Flavobacterium heparinum cultures or else expressed recombinantly, for example in Escherichia coli ([0021]). Klein teaches that the anticoagulant effect of heparins is derived from the formation of complexes with antithrombin (AT), an important plasmatic inhibitor of activated coagulation factors. Klein states that “Antithrombin belongs to the group of serine protease inhibitors (serpins) and inhibits the coagulation factors thrombin (factor IIa, FIIa) and factor Xa (FXa) and, to a small extent, also the other serine proteases FIXa, FXIa, FXIIa, kallikrein and plasmin” ([0004]). Thus, Klein teaches that heparin interferes with coagulation factor activation, including the activity of Factors X, IXa and XIa.
Klein also teaches that the heparinase concentration may be from “0.05 to 5.0 U/ml”, particularly preferably in a concentration of from “0.25 to 1.25 U/ml” in the mixture ([0022]), and that the sample is incubated with a heparin-modifying component preferably for a period of from 10 to 900 seconds at the standard temperature of 37°C ([0023]). Klein teaches that 1 unit of heparinase corresponds to the amount of enzyme required to eliminate 1 μmol of unsaturated oligosaccharides from heparin per minute at 30° C and pH 7.0.
Thus, before the effective filing date of the instant invention, to one of ordinary skill in the art it would have been obvious to modify the method taught in Wolberg for detecting FXIa in IgG-containing preparations derived from plasma samples, as evidenced by Hooper, by treating the samples prior to the FXIa assay with heparinase, as taught in Zimmerman and Klein, in order to remove heparin for preventing heparin-dependent inhibition of the FXIa detecting assays because heparin interferes with FIXa and FXa activity, as taught in Zimmerman and Klein.
One of ordinary skill in the art, from the combination of teachings in the provided references, would have been motivated to eliminate any contaminating heparin in a sample to be tested for FXIa activity, because heparin would, as discussed in Klein and Zimmerman, interfere in the FXIa detection assay used in Wolberg, which depends upon the activity of FIXa and FXa.
One similarly would have desired to have the lowest detection levels (highest sensitivity) of FXI possible, according to the teachings of Wolberg, as this factor can cause thromboembolic events in patients after receiving IgG therapy.
MPEP § 2143 describes that “one rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)…” and: "[I]t can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does." KSR, 550 U.S. at 418, 82 USPQ2d at 1396.
In the instant case, the heparinase of Klein and Zimmerman (eliminating any heparin-dependent inhibition in the plasma sample to be tested) and the Factor XIa detection assay taught in Wolberg with supporting evidence from Hooper (detecting and quantifying Factor XIa activity), would have each been performing the identical functions in the combination as independently. A person of ordinary skill would have been prompted by the combined teachings of the art to combine these elements in order to predictably yield an improved test with improved sensitivity and less chance for a false negative error due to interference of the assay by heparin.
Regarding claim 2, one of ordinary skill in the art would have been instructed by the teachings of Klein to suggest any of heparinase I, heparinase II, and/or heparinase III.
Regarding claim 3, the IVIG commercial preparations taught in Wolberg for assaying FXIa comprise IgG derived from pooled human plasma samples, as taught in Hooper.
Regarding claim 7, Wolberg discloses in vitro activity assays for detecting and quantifying FXIa activity and one would have been motivated to improve upon such an assay, for all of the reasons discussed above.
Regarding claims 8-11, Zimmerman teaches when performing various assays, the elimination of heparin-dependent inhibition at up to 12 IU heparin/ml in the sample. Specific embodiments of Zimmerman include neutralizing 1.0 IU/mL heparin with heparinase. These fall explicitly within the ranges or a value of heparin concentration recited in the instant claims.
Regarding claim 12, the unit “U”- as used in claims 12-15- has been interpreted to mean the International Unit of heparinase activity as described in the specification ([0076]). Zimmerman teaches specific embodiments using 1.5 IU/mL of heparinase (see Table 4, Col 9), but also describes 1.5 IU/mL of heparinase as being equivalent to “100 U/mL” of heparinase (Table 6; Col 10). Klein teaches applying heparinase at a concentration from “0.05 to 5.0 U/ml”. Klein states that 1 unit of heparinase therein corresponds to the amount of enzyme required to eliminate 1 μmol of unsaturated oligosaccharides from heparin per minute at 30° C and pH 7.0. This is consistent with the interpretation of the International Unit as described in the instant specification. Thus, the amount of heparinase taught in Klein substantially overlaps and makes obvious the instantly claimed range of about 0.1 U/mL to 10 U/mL of claims 12. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)… See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941)”.
Regarding the specific amounts of heparinase recited in claims 13 and 14, these amounts (0.2U/mL and 5U/mL, respectively) represent specific embodiments within the range taught in Klein and approximate to the amounts used in Zimmerman. Thus arriving at either of these claimed enzyme concentrations would have merely been a matter of optimizing the amount of heparinase used, within the guidelines of the ranges taught in the prior art, and optimizing this concentration for the parameters of the chosen enzyme. See MPEP § 2144.05, which describes that the determination of suitable or effective concentration of a known composition (or performing a known method) can be determined by one of ordinary skill in the art through the use of routine or manipulative experimentation to obtain optimal results, as these are variable parameters attainable within the art. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In regards to claim 15, for one of ordinary skill, it would have been obvious to arrive at the greater amount of enzyme, that of 10 U/mL recited in claim 15, as one seeking to completely eliminate heparin or optimize the removal of the heparin-dependent inhibition would have been motivated to add an abundance of the enzyme, in order to ensure that the equilibrium of the reaction favors the rapid and efficient degradation of heparin, as suggested within the teachings of Zimmerman, particularly the teachings that heparinase neutralization may be complete within the time required for the enzyme to dissolve and that merely 0.05 IU of heparinase completely neutralizes the heparin in a 0.4 ml whole blood sample containing 4.8 IU heparin in 15 seconds (Col 6, lines 20-32 therein). MPEP § 2144.05(II)(A) establishes that “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955)”.
Regarding claims 16 and 17, Zimmerman teaches that 0.05 IU heparinase completely neutralizes the heparin in a 0.4 ml whole blood sample containing 4.8 IU heparin in 15 seconds. Thus Zimmerman suggests a method wherein the sample is incubated for between 5 sec and 7200 sec (e.g. 15 seconds), wherein the ratio of heparin to heparinase is about 1:0.01. Other specific embodiments in Zimmerman include 1: 0.25 (6 IU/mL heparin to 1.5 IU/mL heparinase, Table 4) and 1:1.5 (1 IU/mL heparin to 1.5 IU heparinase; at col 10 lines 25-30).
Regarding claim 18, the claimed time of 300 seconds (5 min) of treatment falls within the general times taught in Klein, supported by the findings of Zimmerman. Klein discusses incubating the enzymes for a period of from 10 to 900 seconds, of which 300 seconds falls within the range. Arriving at this particular time for optimizing the treatment would have been within the level of ordinary skill in the art. Zimmerman teaches the efficiency of the heparinase enzymes, and thus it would have been predictable to one of ordinary skill in the art that an incubation time of at least 300s would achieve the desired elimination of heparin in the sample.
Regarding claim 19, Zimmerman or Klein do not teach that the sample is incubated for as long as 7200 sec (120 minutes), however, Klein states that the enzyme is allowed to incubate for up to 60 minutes at 4°-37°C. Although the recited element is longer than the times taught in Klein or Zimmerman, when one is seeking to eliminate all of the heparin present as discussed in Zimmerman, one of ordinary skill in the art would have recognized that an increased incubation time is likely to achieve that desired effect. In optimizing the reaction time such that all of the heparin is eliminated, one would have predictably arrived at the instantly claimed 120 minutes (7200 seconds).
In regards to both claims 18 and 19, one of ordinary skill in the art would have been aware of the relationships between the recognized result-dependent variables of such enzyme reactions. These parameters include the concentration of the heparinase, the temperature, and the reaction time, as taught in the art. Thus, even if the specific incubation time is not expressly taught by Zimmerman or by Klein, based upon the overall beneficial teaching provided by these references with respect to the conditions for the activity of the heparinase in the manner disclosed therein, the adjustments of particular conventional working conditions (e.g., determining one or more suitable times, concentrations, or temperature ranges in which to perform the heparin degradation), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan (see MPEP § 2144.05).
Regarding claims 20-22, Klein specifies that the reaction is performed at 37°C, which meets the limitations of all three of the claims. Zimmerman teaches that the reaction may be between 4 and 37°C, but does not exactly specify 37°C. However, based upon the overall beneficial teaching provided by Zimmerman with respect to the conditions for the activity of the heparinase degrading heparin, the adjustments of particular conventional working conditions (e.g., determining one or more suitable times, concentrations, or temperature ranges in which to perform the heparin degradation), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan (see MPEP § 2144.05).
Regarding claim 23, one of ordinary skill would have been motivated by the teachings of Zimmerman and Wolberg to eliminate all of the contaminating heparin. One would have sought to remove all sources of FXIa assay inhibition, in order to properly detect FXIa at the highest level of sensitivity and avoid false negatives. One of ordinary skill would have recognized from Zimmerman that providing of the enzyme at a high enough concentration (i.e. in excess) and at a suitable temperature for long enough incubation would have achieved this goal.
Each of the references are analogous to the instant invention, being from similar fields of processing IgG samples and/or testing plasma samples for coagulation factor activity. Further, both Klein and Zimmerman teach improved blood clotting detection assays following treatment with heparinase to eliminate heparin-dependent inhibition. One having ordinary skill would be capable of obtaining reaction conditions to successfully inactivate and/or eliminate the heparin.
From the cited teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention by providing heparinase to a plasma sample, including IgG-containing plasma samples, when seeking to improve blood coagulation factor detection.
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the cited references, especially in the absence of evidence to the contrary.
Claims 1-4 and 7-23 are rejected under 35 U.S.C. 103 as being unpatentable over “Wolberg” (2000. American Journal of Hematology 65:30-34), Zimmermann et al. (US Pat. No. 5,262,325), Klein et al. (US PGPub No. 20070037236), and Hooper et al. (2008. Immunol Allergy Clin North Am.) as applied to claims 1-3 and 7-23 above, and further in view of Bruckschwaiger et al. (US Pat. No. 8,796,430 to Baxter International Inc.).
Claims 1-3 and 7-23 have been rejected under 35 U.S.C. § 103 as being obvious over the combined teachings of Wolberg, Zimmerman, Klein, and Hooper cited above.
Wolberg teaches a number of commercially available IVIG products that were tested for the presence of Factor XIa therein. Similarly, Hooper provides evidence regarding the commercial IVIG products as of 2008, all of which were plasma-derived and most of which included a step of cold ethanol fractionation/precipitation (see Table 1 therein).
However, none of the cited references recite explicitly that the IgG-containing plasma is derived from cryo-poor plasma as in claim 4.
Bruckschwaiger et al. (US 8,796,430) discloses methods for preparing an enriched IgG compositions (e.g., IVIG compositions) from plasma (Abstract, Claim 1). Bruckschwaiger teaches methods which allow for increased yields of IgG in the final bulk composition without losing the purity required for intravenous administration (Col 3, lines 26-34). Bruckschwaiger teaches specifically methods for preparing an enriched IgG composition from plasma comprising the initial step of (a) precipitating a cryo-poor plasma fraction (Col 3, lines 35-58, Col 9, lines 47-50). Thus, Bruckschwaiger teaches methods for generating an IVIG therapeutic comprising an IgG that is derived from cryo-poor plasma (herein interpreted as a supernatant formed after the precipitation (cryo-precipitation) of plasma or pooled plasma at temperatures near freezing.
Thus, to one of ordinary skill in the art, before the effective filing date of the instant invention, it would have been prima facie obvious to modify the method taught by the combination of Wolberg, Hooper, Zimmerman, and Klein for detecting FXIa in IgG-containing preparations derived from plasma samples by treating the samples prior to the FXIa assay with heparinase to remove heparin for preventing heparin-dependent inhibition of the FXIa detecting assays, to use this method on an IVIG sample derived from cryo-poor plasma as taught and suggested in Bruckschwaiger.
Bruckschwaiger demonstrates the benefits of preparing an enriched IgG composition from plasma comprising the precipitating a cryo-poor plasma fraction, which allows for increased yields of IgG in the final bulk composition without losing the purity required for intravenous administration. Thus, when performing the method taught by the combination of Wolberg, Zimmerman, Klein, and Hooper, one of skill in the art would have been motivated by Bruckschwaiger to select a cryo-poor derived IgG plasma sample as these are known products in the art (even if such a sample is not inherently discussed in Wolberg).
There would have existed a reasonable expectation of success, as evidenced by the teachings of Bruckschwaiger and Wolberg, with further evidence from Hooper in regards to the level of knowledge in the art. The selection of which plasma fraction to provide from among those IVIG products containing IgG which were commonly known at the time would have been a matter of judicial selection to one of ordinary skill in the art, with a reasonable expectation of success according to the cited references, and in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 7/21/2025 in regards to the rejections of claims 1-4 and 7-23 under 35 U.S.C. § 103 have been fully considered but they are not persuasive.
Applicant argues, on page 11, that the Office had not examined the invention as a whole, or instead had characterized “the instantly claimed invention as the elimination of heparin from a plasma sample using heparinase”. As an initial matter, the previous office action did address each and every limitation of the claims, including the use of activity assays (broadly including in vitro and/or in vivo activity assays, as discussed above) to detect activated Factor XI (see page 10, third ¶, and page 14 last ¶ of the non-final rejection). Wolberg teaches measurements of activated Factor XI, as set forth above. Thus, the argument that the previous action distilled the invention down to the “gist” or “thrust” is unpersuasive.
In response to applicant's argument that the references fail to show certain features of the invention (as discussed on pages 11-12 of the remarks), it is noted that the features upon which applicant relies are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues that “an essential element of the claimed invention is contacting FXIa with heparinase in a plasma sample in a manner that allows for the FXIa to be assayed; neither destroyed by heparinase, nor is the assay interfered with by the enzyme”.
This is not actually recited in claim 1, as the claim recites “a) incubating the plasma sample containing heparin with heparinase, essentially eliminating any heparin-dependent inhibition therein, thereby producing a heparin- depleted sample; and b) detecting and/or quantitating FXIa in the sample by measuring activity of activated proteins in the heparin-depleted sample.”
Under the B.R.I. of the claim language, there is no requirement that FXIa is present in the plasma sample that is contacted with heparinase. As the claims are drawn to a diagnostic assay, there is no requirement that the FXIa be present. A situation may arise where the assay can be used on a plasma sample that has no FXIa. Further, the cited art does describe assays for detecting activated Factor XIa in heparinase treated samples, by the use of indirect assays, which are not excluded from the claim 1. Further, Wolberg does teach measurements of activated Factor XI, as set forth above.
Regarding the Applicant’s argument that the “Action does not advance a reference disclosing an assay of any individual plasma protein of any identity following inactivation of heparin in the plasma by treating it with heparinase, nor does the combination disclose that FXIa was known to survive treatment with heparinase”, these elements are not actually required by claim 1. Further, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981).
In response to applicant's arguments against the references individually (as in pages 12-16), one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues that because Wolberg teaches assays on a solution of research grade proteins or any other protein “in a plasma matrix” that it cannot be relied upon to suggest that a solution of research grade protein is an adequate model for the protein in a plasma environment. This argument is unpersuasive, because although claim 1 recites that a plasma sample containing heparin, there is no limitation requiring this to be unpurified plasma or untreated plasma. In fact, claims 3-6 pertain to using samples that are obtained from treated plasma, such that an IgG fraction or a double-depleted cryo-poor plasma (DDCPP) is the supplied sample. Therefore, the term plasma sample, as recited in claim 1, encompasses purified IgG samples such as those discussed explicitly in Wolberg. And, as evidenced in the cited review Hooper, IgG preparations, such as those intended for commercial applications which encompasses those of the instant invention, (see [0001]-[0003] and [0060] of the specification) are almost always derived from plasma samples ([0060] states “the term "Intravenous IgG" or "IVIG" treatment refers generally to a therapeutic method of intravenously, subcutaneously, or intramuscularly administering a composition of IgG immunoglobulins to a patient for treating a number of conditions such as immune deficiencies, inflammatory diseases, and autoimmune diseases. The IgG immunoglobulins are typically pooled and prepared from plasma”). Thus, Applicant’s argument that Wolberg does not teach the measurement of activity Factor IXa from complex plasma samples is unpersuasive, as the instant claims do not require such particular teaching.
Applicant also argues that Zimmerman does not teach an assay for detecting or quantifying the amount of any single blood clotting factor (see pages 14-16) and thus cannot be used to support the combination applied in the rejection. However, this is not persuasive as Zimmerman has been relied upon for the teachings cited above, which include the facts, that are not argued by the Applicant, that heparin interferes with assays for clotting factors, and that heparinase can successfully be used to remove the interfering heparin. There is no requirement that a secondary reference teach all of the elements of the instant claim. In fact, the primary reference Wolberg teaches assays for individual clotting factors. MPEP 2141.II.C states that "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton."KSR, 550 U.S. at 421, 82 USPQ2d at 1397. "[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle."Id. at 420, 82 USPQ2d at 1397. Office personnel may also take into account "the inferences and creative steps that a person of ordinary skill in the art would employ."Id. at 418, 82 USPQ2d at 1396.
Further, claim 1 does not require a direct assay of FXIa, just “measuring activity of activated proteins in the heparin-depleted sample.”, which is performed in Zimmerman.
The instant application, in the specification states that the assay may be “any in vivo or in vitro assays to determine procoagulant activity, amidolytic activity or Factor XI zymogen… FXIa activity assays include thrombin generation assay (TGA), non-activated partial thromboplastin time (NAPTT) assay, FXIa determination with a Factor IX (FIX) based assay, in vivo Wessler test, FXIa chromogenic assay, ELISA assay.” As the instantly recited assays include those testing for clotting time (i.e. the non-activated partial thromboplastin time (NAPTT) assay and the in vivo Wessler test), the argument that the teachings of Zimmerman as being unapplicable to the instant invention is unpersuasive. One having ordinary skill in the art would understand that the general teachings of Zimmerman regarding the interference of heparin would be applicable to any assay from blood or plasma-derived samples that one may wish to undertake. As such activity assays are taught in Wolberg, on plasma-derived samples of IgG, the application of heparinase to remove heparin would have been obvious, as indicated previously.
The applicant also argues that Hooper is irrelevant to the claims FXIa assay, however, this argument is found unpersuasive. Hooper is related to the instant invention by the nexus of the use of the FXIa assay in the preparation of commercial IVIG products as described in the instant invention, see [0001]-[0005] of the specification, and further by the subject matter of claims 3-6 which pertain directly to IgG preparations.
It has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, Hooper pertains to IgG preparations for therapeutic purposes, which appears to be a major intended target substance for the claimed assay of the instant invention. Thus it is reasonably pertinent to the problem at hand (as also pertinent to the detection assays taught in Wolberg).
Finally, in regards to the arguments about Klein, Klein has been cited as providing teachings regarding properties of heparin, how it is known to interfere with certain clotting factors, including Factor XI, and how particular concentrations of heparinase are applied to inhibit heparin. One having ordinary skill in the art would expect from the combined teachings of Klein and Zimmerman that heparin is an interferent in assays of clotting activity and needs to be eliminated, and would turn to the art for guidance in determining effective concentrations. The argument that the unit of activity is different in Klein is inconsequential, as one having ordinary skill in the art would know that enzyme concentration is a major result-effective variable in success of an enzyme-based treatment, and thus arriving at a concentration (regardless of the unit definition, which is not actually recited in the claim) would be a matter of routine optimization.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, as set forth previously, Wolberg teaches individual factor activity assays, including Factor XI assays, in IgG preparations that were derived from plasma (as indicated by the teachings of Hooper and which are also specified in the instant claims 3-6), and Zimmerman and Klein teach removing assay-interfering heparin through the application of heparinase.
Regarding Applicant’s argument that the combination does not disclose all claim elements (see page 18), because the combination does not disclose or suggest "detecting and/or quantitating FXIa in the sample by measuring activity of activated proteins in the heparin-depleted sample", and that none of the references disclose or suggest detection of any individual plasma protein in a heparin-depleted plasma sample, this argument has been fully considered by is considered unpersuasive, for the same reasons set forth above. The claim language does not require that the individual plasma protein is quantified, just “detecting and/or quantitating FXIa in the sample by measuring activity of activated proteins”. Such detecting is accomplished by the assays set forth in Wolberg. The IgG samples of Wolberg appear to be, lacking evidence to the contrary, derived from plasma samples and are thus essentially the same as the IgG samples recited in the instant claim 3 (dependent on claim 1). The elimination of heparin is taught in Zimmerman and thus the combination of a heparinase treatment with the assays taught in Wolberg would have been obvious to one of ordinary skill in the art.
Applicant’s argument that the combination fails to provide a reasonable expectation of success because “the combination of references fails to suggest that FXI in plasma would survive treatment with heparinase” has been fully considered but is not persuasive.
Applicant states that: “Where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success. The reasonable expectation of success requirement refers to "the likelihood of success" in combining or modifying prior art disclosures to meet the limitations of the claimed invention. See Elekta Ltd. v. ZAP Surgical Sys., Inc., 81 F.4th 1368, 1375, 2023 USPQ2d 1100 (Fed. Cir. 2023) and Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359, 1367, 119 USPQ2d 1171, 1176 (Fed. Cir. 2016).”
In the instant case, the cited references Zimmerman and Klein demonstrate that the issue of heparin interference is known to the art, and that application of heparinase is an established solution to the problem. The use of heparinase, coupled with the ordinary level of skill in enzymology and in blood/plasma product preparation would have had a predictable level of success in eliminating any residual heparin in a plasma-derived sample to be tested. The Applicant argues that the reference do not show that FXI in plasma survives treatment with heparinase in unpersuasive, because Zimmerman shows the successful testing of clotting time after heparinase treatment. As FXI is one of the factors necessary for clotting it stands to reason that FXI (and other clotting factors) remain present and active, at least at a minimal amount, after the heparinase treatment. Further, the claim language does not require that FXI (or FXIa) is present in the sample, just that the assay tests for FXI. As stated by the Applicant, one having ordinary skill in the art would understand that blood coagulation factor assay conditions need to be particularly customized for desired accuracy. Therefore, the adjustments of working conditions, or concentrations of enzymes and substrate, would be within the ordinary level of skill in the art, and there would be a reasonable expectation of success in doing so. MPEP § 2143.02 establishes that “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) ("To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring ‘absolute predictability of success.’"); Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). Here, there appears to be a reasonable expectation of success, when considering the knowledge in the art for factor FXIa assays (as in Wolberg) and the application of heparinase (as in Zimmerman).
Applicant’s argument that the claimed process provides surprisingly accurate FXIa measurements, on pages 19-20, has been fully considered, and is not persuasive for claims 1-4 and 7-23, which do not require the specific FXIa Chromogenic assay steps that are used in the example experiment cited by the applicant. Claim 1 recites “by measuring activity of activated proteins in the heparin-depleted sample”, and claim 7 recites “wherein the detecting and/or quantitating in b) further comprises running an in vitro or an in vivo activity assay for FXIa”. These do not require all of the steps used in [0080]-[0094] of the specification and the unexpected results cannot be said to be generally applicable to any and all assay configurations which may be encompassed by these claims. Thus, this argument is found unpersuasive for the rejections as they pertain to claims 1-4 and 7-23.
The amended claim 24 requires particular steps used in the FXIa Chromogenic assay embodied in these examples, and thus the evidence of unexpected success is relevant to the invention of claim 24. After considering these arguments, and other secondary considerations in view of the claim as a whole, the rejection of claim 24 as being obvious has been withdrawn, as further discussed below.
Allowable Subject Matter
Claims 5, 6, and 24 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The subject matter of claims 5 and 6 is drawn to treatment of an IgG derived from IgG derived from a plasma supernatant after C1-esterase inhibitor adsorption of cryo-poor plasma and to a plasma sample comprising an IgG derived from a double-depleted cryo-poor plasma (DDCPP) after C1-esterase inhibitor adsorption, which are not taught in the relevant prior art.
As these particular treatments to cryo-poor plasma are not explicitly taught nor suggested by the prior art, the use of the heparinase and Factor XIa activity assays on cryo-poor plasma containing IgG after C1-esterase inhibitor adsorption would thus not have been obvious.
The related U.S. Patent Application 17/907,536, published as US 2023/0142480, shares an Applicant with the instant application, but has a later effective filing date. Application ‘536 discusses the use of a cryo-poor plasma supernatant after C1- esterase inhibitor adsorption, wherein said cryo-poor plasma fraction is depleted of C1-INH by at least about 70% of total present in the cryo-poor plasma fraction ([0056]) and teaches use of a double depleted cryo-poor plasma (DDCPP) to yield a product comprising IgG (see [0063] - [0065]). Both Application ‘536 and the instant specification state that C1-inhibitor depleted supernatant fraction is generally not considered an ideal starting material for the manufacture of IgG as depletion of C1-INH results in accumulation of plasma kallikrein, Factor XIa, and Factor XIIa, which are undesired contaminants ([0090] in ‘536; [0074] in the instant specification). However, the claims of the ‘536 application are not drawn to detection of Factor XIa nor the use of heparinase.
Regarding claim 24, the Applicant’s argument of unexpected performance when performing this specific method (i.e. when using the “FXIa Chromogenic assay” as stated in the Applicant’s argument) is persuasive, in view of the arguments and data presented in the application. As these specific steps, when performed in order with the heparinase assay, result in unexpected success, the previous rejection of claim 24 as being obvious is herein withdrawn.
Conclusion
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.
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ANDREW T MOEHLMANExaminer, Art Unit 1655
/TERRY A MCKELVEY/Supervisory Patent Examiner, Art Unit 1655