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 .
Status of the claims
The Preliminary Amendment filed 07/31/24 is acknowledged and has been entered. Claims 3-6, 9-12 and 15-17 have been amended. Currently, claims 1-17 are pending and under examination.
Specification
The use of the term Tween 20 (e.g. page 12, lines 24-30), which is a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-12 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and/or to laws of nature/natural phenomena without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims are directed to a naturally occurring correlation between antibodies against PF4 and VITT or s-HIT.
Step 2A, Prong 2
The additional elements of contacting an uncomplexed PF4 polypeptide with sample and detecting the presence or absence of antibody-uncomplexed PF4 polypeptide does not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Also, with respect to the recitation “wherein the presence of said antibody-ucomplexed PF4 polypeptide complexes indicates that said mammal has VITT; and wherein the absence of said antibody-uncomplexed PF4 polypeptide complexes indicates that said small does not have VITT”. The “wherein” statement at best articulates the judicial exception, amounting only to a general instruction to apply or use the judicial exception. This could read on mental activity being performed solely in a practitioner’ head, e.g. A mental appreciation of the recited complexes being correlated with a population of subjects. No active method steps are invoked or clearly required; the “identifying” statements do not include any activity that would constitute a practical application, i.e. steps that apply, rely on or use the natural principle in a manner such that the claims amount to significantly more that the natural principal itself.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Further, the additional elements of the claims are recited with a high level of generality and do not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. (the active method steps/limitations recited in addition to the judicial exceptions themselves) and do not add significantly more to the judicial exception(s).
As shown by the art below it is well known routine and conventional in the art to contact a sample from a patient with uncomplexed PF4 polypeptide and to detect the presence or absence of antibody-uncomplexed PF4 polypeptide complexes.
With respect to “administering to said mammal intravenous immunoglobulin G (VIg)….” as recited in claims 5 and 11. Although the claim invokes administering a medicament to the mammal the claim as currently recites “when the presence of said antibody-uncomplexed PF4 polypeptide complexes is detected” The recitation of “when” allows for the scenario when the level is below a reference level indicating the subject is not at risk and thus allows for an embodiment wherein no medicament is administered. Therefore, this scenario does not recite something significantly more than the judicial exception.
It does not appear to be the case that the active steps recited, which are performed in order to gather the data or perform the assay, are steps recited or performed in an unconventional or non-routine way, such to provide an inventive concept under step 2B.
The claimed limitations as currently presented fail to recite limitations that add a feature that is more than well understood, conventional or routine in the field of diagnostics and biochemical assay methodologies.
For all of these reasons, the claims fail to include additional elements that are sufficient to either integrate the judicial exception(s) into practical application(s) thereof, or amount to significantly more than the judicial exception(s).
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Written Description
Claims 1-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are directed to methods for detecting the presence of antibodies to uncomplexed PF4 in any and all samples from any and all mammals and being correlated with VITT. The limitation 'mammal’ represents a genus and encompasses human and non-human including mouse, monkey, dog, rat, pig, kangaroo, horse, canine and feline to name a few. The limitation ‘sample’ represents a genus and encompasses tears, semen, liver, urine, kidney, brain, peritoneal fluid, sputum, synovial fluid, lung tissues or vomit. However, there is inadequate written description in the instant specification for a method of such broad scope as claimed currently.
In order to fulfill the written description requirements set forth under 35 U.S.C § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, each member correlated with the requisite function, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicants have possession the claimed invention. Applicants have not described and established structure-function correlation for a representative number of species within the broad genus of at least the recited ‘mammal’ and ‘sample’ such that the specification might reasonably convey to the skilled artisan that Applicants had possession of the full scope of the claimed invention at the time the application was filed.
The purpose of the written description requirement is ‘to ensure that the inventor had possession, as of the filing date of the application relied on, of the specific subject matter later claimed by him.’ In re Edwards, 568 F.2d 1349, 1351-52, 196 USPQ 465, 467 (CCPA 1978). Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. When there is substantial structural variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
A review of the instant specification indicates the following. The specification on page 7 discloses the detection of reactivity of serum sample from patients (all of which appear to be human) having true VITT. The specification on page 9 discloses the methods provided herein can include contacting a sample such as blood, serum or plasma from a mammal such as a human. Page 12, Example 1 discloses incubating serum or plasma samples with PF4 and the use of labeled anti-human IgG. Page 13 discloses that these studies demonstrated that in the uncomplexed PF4 ELISA, sample from VITT patients had significantly higher OD than samples from patients (which appear to be human) with HIT. Pages 18-19, Example 3 discloses Human Papilloma Virus vaccine and VITT antibody induction. The specification on page 21 discloses obtaining serum samples from patients (which appears to be human) and testing for antibodies. The examples in the specification all appear to be directed to patients that are human and the detection of the recited antibodies in either, blood, serum or plasma from patients with VITT. The specification does not provide data, testing or examples with a showing that any all and all samples from any and all mammals provide the recited biomarkers at levels which can be specifically correlated with VITT. Also, Torzewski et al, (Hindawl Publishing Corporation, Mediators of Inflammation, Vol 2014, Articles ID 683598, pages 1-7) teaches for example that CRP (biomarker) is an acute phase reactant in humans but not an acute phase reactant in a mouse (e.g. page 1). Van Der Vekens et al., (Cardiovascular Endocrinology, 2013, Vol 2, No. 4,pages 67-76) teaches that markers between human and equine show important species differences, which can be explained by variations in physiology or pathophysiology and also teaches pathological differences in the species (e.g. abstract).
The only examples utilized in the specification appears to be limited to patients that are human and the detection of the recited antibodies in either blood, serum or plasma samples from the patients having VITT. The specification does not disclose that the recited antibodies which appear in blood, serum or plasma also appear in samples such as stool, tears lung, brain, sputum, plural fluid etc. or that such antibodies would be expected to be shed, excreted into or found in these samples and correlated with VITT. As stated supra the specification appears to be limited to limited to patients that are human and the detection of the recited antibodies in either blood, serum or plasma samples from the patients having VITT.
The specification also fails to provide for a correlation of the recited antibodies in all mammals such as dogs, cats, cows, monkey, horse, rabbit, squirrel and mice (as shown supra by Torzewski and Van Der Vekens different species of mammal have different expression of biomarkers and do not correlate to the same condition/disease) The specification also fails to provide that the recited antibodies exist in samples such as lung tissue, kidney tissue, stool, saliva, tears, sputum, CSF or liver tissue or that a correlation of these antibodies exist in such mammals with VITT. Further, it is not well known in the art that these samples provide for the recited antibodies and that a correlation exists between such antibodies in the samples with VITT. The examples in the specification appear to be limited to patients that are human and the detection of the recited antibodies in either blood, serum or plasma samples from the patients having VITT. The purpose of the ‘written description; requirement is broader than to merely explain how to ‘make and use’, Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention.
It must be noted that "[t]he applicant must . . . convey to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention." Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir.1991). The invention, is for purposes of the ‘written description’ inquiry, whatever is now claimed.” See page 1117. The specification does not describe the claimed embodiments in sufficient detail to convey to a person skilled in the art that Applicants were in possession of the full scope of the claimed invention at the time of filing. The Written Description Guidelines state: There is an inverse correlation between the level of predictability in the art and the amount of disclosure necessary to satisfy the written description requirement. For example, if there is a well-established correlation between the structure and function in the art, one skilled in the art will be able to reasonably predict the complete structure of the claimed invention from its function. Furthermore, the written description provision of 35 U.S.C § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, paragraph 1, ‘Written Description’ Requirement (66 FIR 1099-1111, January 5,2001) state, ‘[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention’ (Id. at 1104). Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. Factual evidence of an actual reduction to practice has not been disclosed in the instant specification, nor has Applicant shown the invention was ‘ready for patenting’. The Guidelines further state, ‘[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus' (Id. at 1106). For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. Instant claims are viewed as not meeting the written description provision of 35 U.S.C § 112, first paragraph. The specification fails to disclose the detection of the recited biomarkers in any and all biological samples from any and all patients wherein lower levels of the biomarkers are directly correlated with RRMS.
Scope of Enablement
Claims 1-17 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for diagnosing/treating VITT in a human subject that has thrombocytopenia, thrombosis, or both thrombocytopenia and thrombosis comprising detecting antibody-uncomplexed PF4 polypeptide complexes in serum, blood or plasma. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Enablement requires that the specification teach those in the art to make and use the invention without undue experimentation. The factors that must be considered in determining undue experimentation are set forth in In re Wands USPTQ2d 14000. Factors to be considered in determining whether a disclosure would require undue experimentation include (1) the nature of the invention, (2) the state of the prior art, (3) the predictability or lack thereof in the art, (4) the amount of direction or guidance present, (5) the presence or absence of working examples, (6) the quantity of experimentation necessary, (7) the relative skill of those in the art, and (8) the breadth of the claims.
The instant claims are directed to methods for detecting the presence of antibodies to uncomplexed PF4 in any and all samples from any and all mammals and being correlated with VITT.
One cannot extrapolate the teaching of the specification to the enablement of the claims because other than detecting B2MG in a human serum or plasma sample and comparing to a control survivor patient suffering from cardiogenic shock and determining an increased level as compared to the control as indicating mortality risk in the patient.
A review of the instant specification indicates the following. The specification on page 7 discloses the detection of reactivity of serum sample from patients (all of which appear to be human) having true VITT. The specification on page 9 discloses the methods provided herein can include contacting a sample such as blood, serum or plasma from a mammal such as a human. Page 12, Example 1 discloses incubating serum or plasma samples with PF4 and the use of labeled anti-human IgG. Page 13 discloses that these studies demonstrated that in the uncomplexed PF4 ELISA, sample from VITT patients had significantly higher OD than samples from patients (which appear to be human) with HIT. Pages 18-19, Example 3 discloses Human Papilloma Virus vaccine and VITT antibody induction. The specification on page 21 discloses obtaining serum samples from patients (which appears to be human) and testing for antibodies. The examples in the specification all appear to be directed to patients that are human and the detection of the recited antibodies in either, blood, serum or plasma from patients with VITT. The specification does not provide data, testing or examples with a showing that any all and all samples from any and all mammals provide the recited biomarkers at levels which can be specifically correlated with VITT. Also, Torzewski et al, (Hindawl Publishing Corporation, Mediators of Inflammation, Vol 2014, Articles ID 683598, pages 1-7) teaches for example that CRP (biomarker) is an acute phase reactant in humans but not an acute phase reactant in a mouse (e.g. page 1). Van Der Vekens et al., (Cardiovascular Endocrinology, 2013, Vol 2, No. 4,pages 67-76) teaches that markers between human and equine show important species differences, which can be explained by variations in physiology or pathophysiology and also teaches pathological differences in the species (e.g. abstract).
The only examples utilized in the specification appears to be limited to patients that are human and the detection of the recited antibodies in either blood, serum or plasma samples from the patients having VITT. The specification does not disclose that the recited antibodies which appear in blood, serum or plasma also appear in samples such as stool, tears lung, brain, sputum, plural fluid etc. or that such antibodies would be expected to be shed, excreted into or found in these samples and correlated with VITT. As stated supra the specification appears to be limited to limited to patients that are human and the detection of the recited antibodies in either blood, serum or plasma samples from the patients having VITT.
The specification also fails to provide for a correlation of the recited antibodies in all mammals such as dogs, cats, cows, monkey, horse, rabbit, squirrel and mice (as shown supra by Torzewski and Van Der Vekens different species of mammal have different expression of biomarkers and do not correlate to the same condition/disease) The specification also fails to provide that the recited antibodies exist in samples such as lung tissue, kidney tissue, stool, saliva, tears, sputum, CSF or liver tissue or that a correlation of these antibodies exist in such mammals with VITT. Further, it is not well known in the art that these samples provide for the recited antibodies and that a correlation exists between such antibodies in the samples with VITT. The examples in the specification appear to be limited to patients that are human and the detection of the recited antibodies in either blood, serum or plasma samples from the patients having VITT. Thus, one cannot practice the claimed invention without undue experimentation.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 7-10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huynh et al (Nature, Vo 596, 26 August 2021, pages 565-569) (submitted in the IDS filed 03/12/25).
Huynh et al discloses a method comprising contacting a sample from patients having VITT with wild-type PF4 or PF4 mutants (uncomplexed PF4) and incubating to allow for the formation of complexes between the PF4 and anti-PF4 antibodies (e.g. page 269+ (i.e. 270) 2nd col top paragraph). Huynh et al discloses adding alkaline-phosphatase-conjugated goat anti-human IgG and measuring OD to assess the binding of antibodies to the PF4 (ELISA assay). Huynh et al discloses that the patients can have thrombocytopaenia and thrombosis without exposure to heparin (e.g. abstract, page 565; 2nd col). Huynh et al discloses that samples from VITT patients had antibodies against PF4. Huynh et al discloses that VITT is a rare adverse effect of COVID19 adenoviral vector vaccine and that VITT resemble heparin-induced thrombocytopaenia (HIT) in that is associated with platelet-activating antibodies against PF4; however patients with VITT develop thrombocytopaenia and thrombosis without exposure to heparin (abstract). Huynh et al discloses that the sample can be serum (e.g. pgs 568, 569+ and extended data Fig 3). Huynh et al discloses the patient is human (e.g. abstract, pg 268; first col and 569+ with the use of anti-human IgG – thus detecting human antibodies).
Claims 13-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chen et al (Medical Journal of Australia, 215(6), 20 September 2021, pages 245-249.e1).
Chen et al discloses methods for treating VITT comprising administering IVIg or non-heparin anticoagulant to a patient that is identified as having VITT (e.g. pages 247-248). Chen et al discloses that the patients with a positive ELISA result is used to confirm diagnosis (e.g. page 247). Chen et al discloses that the ELISA can be an antigen assay using PF4 (uncomplexed PF4) wherein a sample from the patient is contacted with the PF4 to detect antibodies against the PF4 (e.g. pages 246-247). Chen et al discloses the sample can be a blood sample (e.g. page 246). Chen et al discloses monitoring platelet counts or D-dimer to assess the VITT (e.g. page 248).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
Claims 1-4 and 7-10 are rejected under 35 U.S.C. 103 as being unpatentable over Huynh et al (Nature, Vo 596, 26 August 2021, pages 565-569) (submitted in the IDS filed 03/12/25) in view of Warkentin et al (Thrombosis Research, 204, 2021, pages 40-51).
Huynh et al discloses a method comprising contacting a sample from patients having VITT with wild-type PF4 or PF4 mutants (uncomplexed PF4) and incubating to allow for the formation of complexes between the PF4 and anti-PF4 antibodies (e.g. page 269+ (i.e. 270) 2nd col top paragraph). Huynh et al discloses adding alkaline-phosphatase-conjugated goat anti-human IgG and measuring OD to assess the binding of antibodies to the PF4 (ELISA assay). Huynh et al discloses that the patients can have thrombocytopaenia and thrombosis without exposure to heparin (e.g. abstract, page 565; 2nd col). Huynh et al discloses that samples from VITT patients had antibodies against PF4. Huynh et al discloses that VITT is a rare adverse effect of COVID19 adenoviral vector vaccine and that VITT resemble heparin-induced thrombocytopaenia (HIT) in that is associated with platelet-activating antibodies against PF4; however patients with VITT develop thrombocytopaenia and thrombosis without exposure to heparin (abstract). Huynh et al discloses that the sample can be serum (e.g. pgs 568, 569+ and Fig 3). Huynh et al discloses the patient is human (e.g. abstract, pg 268; first col and 569+ with the use of anti-human IgG – thus detecting human antibodies).
Huynh et al differs from the instant invention in failing to teach the method is for distinguishing vaccine-induced immune thrombotic thrombocytopenia (VITT) from spontaneous heparin-induced thrombocytopenia (s-HIT), and wherein the absence of said antibody-uncomplexed PF4 polypeptide complexes indicates that said mammal has s-HIT.
Warkentin discloses vaccine-induced immune thrombotic thrombocytopenia (VITT) features unusual thromboses similar to those seen in spontaneous heparin-induced thrombocytopenia (s-HIT) syndrome that are heparin- independent, while HIT is usually triggered by a proximate immunizing exposure to heparin (Abstract - "Heparin-induced thrombocytopenia (HIT) serologically by platelet-activating anti-platelet factor 4 (PF4)/heparin antibodies HIT is usually triggered by a proximate immunizing exposure to heparin COVID-19 adenoviral vector vaccination has been associated with a thrombotic thrombocytopenic disorder associated with positive PF4-dependent enzyme-immunoassays and serum-induced platelet activation that is maximal when PF4 is added. Vaccine-induced immune thrombotic thrombocytopenia (VITT) features unusual thromboses similar to those seen in spontaneous HIT syndrome. HIT reflects platelet-activating anti-PF4/heparin antibodies whereas spontaneous HIT syndrome and other atypical "autoimmune HIT" presentations reflect heparin-independent platelet-activating anti-PF4 antibodies'), and wherein HIT syndrome featured of forming PF4 complexed with heparin (antigen), while the polyanion is absent with spontaneous HIT (s-HIT) syndrome (pg 42, para 2 'Fig. 2 shows the interrelationship between HIT, aHIT, and spontaneous HIT syndrome. in the case of HIT, the antigen is PF4 complexed with heparin; in the case of aHIT, the antigen is PF4 in the (relative) absence of polyanion'; pg 42, col 2, para 1 Spontaneous HIT syndrome is a subtype of "autoimmune HIT"(aHIT)'; pg 42, col 2, para 3 - 'indicated by Fig. 2, most cases of aHIT are triggered by heparin; however, "spontaneous HIT syndrome" can be viewed as an aHIT disorder triggered by some environmental trigger'), because there is no sufficient concentrations of the polyanion in circulating blood to lead to sufficient quantities of PF4/polyanion/IgG immune complexes to produce platelet activation (complex formation) for spontaneous HIT (s-HIT) (pg 42, col 2, last para - 'consistent finding of spontaneous HIT syndrome is the detectability of antibodies that activate platelets in the absence of heparin but are inhibited by high concentrations of heparin (10-100 U/mL). occurrence of thrombocytopenia in most cases, as it is doubtful there would be sufficient concentrations of the polyanion in circulating blood to lead to sufficient quantities of PF4/polyanion/IgG immune complexes to produce platelet activation').
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to combine the teachings of Huynh and Warkentin, to obtain a method for detecting vaccine-induced immune thrombotic thrombocytopenia (VITT), wherein said method comprises: (a) contacting an uncomplexed PF4 polypeptide with a sample from a mammal that (i) has thrombocytopenia, thrombosis, or both thrombocytopenia and thrombosis, and (ii) does not have heparin-induced thrombocytopenia (HIT), wherein antibody-uncomplexed PF4 polypeptide complexes form if said sample contains VITT antibodies, and wherein antibody-uncomplexed PF4 polypeptide complexes do not form if said sample does not contain VITT antibodies, and (b) detecting the presence or absence of antibody-uncomplexed PF4 polypeptide complexes, wherein the presence of said antibody-uncomplexed PF4 polypeptide complexes indicates that sald mammal has VITT, as taught by Huynh, and further the method is for distinguishing vaccine-induced immune thrombotic thrombocytopenia (VITT) from spontaneous heparin-induced thrombocytopenia (s-HIT), and wherein the absence of said antibody-uncomplexed PF4 polypeptide complexes indicates that said mammal has s-HIT, based on the combination of Warkentin and Huynh, in order to combine methods, technologies, and knowledge available in the art for facilitating distinguishing thrombocytopenia that are not triggered by heparin, including distinguishing vaccine-induced immune thrombotic thrombocytopenia (VITT) from spontaneous heparin-induced thrombocytopenia (s-HIT) with desired effectiveness with an expected success and without undue experimentation.
Claims 5-6, and 11-17 are rejected under 35 U.S.C. 103 as being unpatentable over Huynh et al in view of Warkentin et al as applied to claims 1-4 above, and further in view of Chen et al (Medical Journal of Australia, 215(6), 20 September 2021, pages 245-249.e1).
See above for the teachings of Huynh et al and Warkentin et al.
Huynh et al and Warkentin et al differ from the instant invention in failing to teach administering a non-heparin anticoagulant and also fails to teach monitoring platelet count or D-dimer levels.
Chen et al teaches that it is known and conventional in the art when testing for VITT to perform an ELISA test for anti-PF4 antibodies and to administer non-heparin anticoagulant and IVIg to treat suspected VITT patients (p. 248). Chen et al also teaches that platelet count and D-dimer levels should be monitored until D-dimer levels fall (e.g. p. 248).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to administer a treatment such as taught by Chen et al to the patients in the modified method of Huynh et al and to also monitor platelet counts and/or D-dimer in the patients because Chen et al shows that it is known and conventional in the art and that when VITT is probable treatment should be initiated urgently (e.g. pg 249). Thus, one of ordinary skill in the art would have a reasonable expectation of success administering a treatment and monitoring of platelet count or D-dimer in the patients of the modified method of Huynh et al.
Claims 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over Huynh et al in view of Chen et al (Medical Journal of Australia, 215(6), 20 September 2021, pages 245-249.e1).
See above for the teachings of Huynh et al.
Huynh et al differs from the instant invention in failing to teach administering a non-heparin anticoagulant and also fails to teach monitoring platelet count or D-dimer levels.
Chen et al teaches that it is known and conventional in the art when testing for VITT to perform an ELISA test for anti-PF4 antibodies and to administer non-heparin anticoagulant and IVIg to treat suspected VITT patients (p. 248). Chen et al also teaches that platelet count and D-dimer levels should be monitored until D-dimer levels fall (e.g. p. 248).
It would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to administer a treatment such as taught by Chen et al to the patients in the method of Huynh et al and to also monitor platelet counts and/or D-dimer in the patients because Chen et al shows that it is known and conventional in the art and that when VITT is probable treatment should be initiated urgently (e.g. pg 249). Thus, one of ordinary skill in the art would have a reasonable expectation of success administering a treatment and monitoring of platelet count or D-dimer in the patients of the method of Huynh et al.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY W COUNTS whose telephone number is (571)272-0817. The examiner can normally be reached M-F 7:00-4:00.
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/GARY COUNTS/ Primary Examiner, Art Unit 1678
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