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 .
Claim Rejections - 35 USC § 112
Claims 1-13 and 20 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
The claims require a capture agent that binds to IL-6 (see for example claim 1, lines 4-5). The specification does not describe which amino acid residues, nucleic acid residues or other molecular components are responsible for the functions claimed. Rather, the specification states that these potential agents must first be screened in an assay to ascertain if the agents have the functions required by the instant claims. Although the specification provides a few examples of potential generic agents, it fails to disclose the structures common to all members of the genus of peptides encompassed by the broad definition provided by applicant. The specification does not disclose the structure of all of the claimed variant agents and fails to disclose which regions of the agents are responsible for the functions claimed. In the absence of a known or disclosed correlation between structure and function, claims which encompass variants defined by their function are generally not considered described.
Applicant is directed to MPEP § 2163 for guidelines on compliance with the written description requirement. Here, applicant has not described a reasonable number of members of the genus of agents that bind to IL-6, i.e. the required starting materials for the claims, but rather has presented the public with an idea of how to perform an assay that might identify some peptides that fall within the scope of the claim. Of course, depending on what agents are used in the screening assay, it may well identify none. The Court of Appeals for the Federal Circuit addressed claims of this sort in great detail in University of Rochester v. G.D. Searle and Co. (69 USPQ 2nd 1886, CAFC 2004). In Rochester, the Federal Circuit upheld the district court's ruling that patent claims which recited administration of compounds not disclosed, but rather to be identified in a screening assay, were invalid on their face.
Regarding the scope of the claims that includes antibodies that bind to IL-6, the specification does not describe the structure of the full genus of antibodies responsible for each of the functions claimed. The Federal Circuit has clarified Written Description as it applies to antibodies in the recent decision Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017). The Federal Circuit explained in Amgen that when an antibody is claimed, 35 U.S.C. 112(a) (or pre-AIA first paragraph) requires adequate written description of the antibody itself. Amgen, 872 F.3d at 1378-79. The Amgen court expressly stated that the so-called “newly characterized antigen” test, which had been based on an example in USPTO-issued training materials and was noted in dicta in several earlier Federal Circuit decisions, should not be used in determining whether there is adequate written description under 35 U.S.C. 112(a) for a claim drawn to an antibody. Citing its decision in Ariad Pharmaceuticals, Inc. v. Eli Lilly & Co., the court also stressed that the “newly characterized antigen” test could not stand because it contradicted the quid pro quo of the patent system whereby one must describe an invention in order to obtain a patent. Amgen, 872 F.3d at 1378-79, quoting Ariad, 598 F.3d 1336, 1345 (Fed. Cir. 2010). In view of the Amgen decision, adequate written description of an antigen alone is not considered adequate written description of a claimed antibody to that antigen, even when preparation of such an antibody is routine and conventional. Id.
While generically the structure of antibodies is known, the structure of the presently recited antibodies can vary substantially within the above given claimed recitations. As noted in Amgen, knowledge that an antibody binds to a particular epitope on an antigen tells one nothing at all about the structure of the antibody, wherein “instead of analogizing the antibody-antigen relationship to a ‘key in a lock,’ it [is] more apt to analogize it to a lock and ‘a ring with a million keys on it.” (Internal citations omitted). The relevant antibody art confirms this quandary, indicating that “knowledge of an epitope or antigen used to generate a monoclonal antibody is insufficient for making the original antibody available, even if suitable in vitro test systems for screening are used.” See p. 8, lines 3-5 of WO 2009/033743 A1.
Therefore, those of skill in the art would not accept that the inventor had been in possession of the full genus of antibodies presently claimed.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. Abbvie Deutschland GMBH & Co. v. Janssen Biotech, Inc. (759 F.3d 1285 (Fed. Cir. 2014). “When a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus." Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005).
Consequently, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus of binding agents (including antibodies) nor guidance as to which of the myriad of molecules encompassed by the binding agents would meet the limitations of the claims. Further, given the well-known high level of polymorphism of immunoglobulins and antibodies, the skilled artisan would not have recognized that applicant was in possession of the vast repertoire of antibodies encompassed by the claimed invention.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111 (Fed. Cir. 1991), clearly states that “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. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed.” (See page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116).
The skilled artisan cannot envision the detailed chemical structure of the genus of binding agents, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of identification. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). Therefore, the instant claims do not meet the written description provision of 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph.
Claim Rejections - 35 USC § 103
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.
Claim(s) 1-7 and 9-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 20150285793 (hereinafter “Chan”) in view of US 20030114377 (hereinafter “Kirkland”).
Chan discloses the following limitations of Applicant’s claim 1.
Chan discloses a device [see para. 0070 disclosing a test device] comprising:
a membrane member having a first surface and a second surface [see para. 0070 disclosing a reaction zone 3].
Claim 1 also recites that the membrane member comprises two stacked nitrocellulose membrane layers, each having pores of about 0.2 um.
See Chan on paragraph 0057 disclosing that the term “absorbent zone” is intended to include one or more layers of a permeable (e.g. porous or fibrous) material, which layers can be the same or different, and are capable of drawing or wicking fluid by capillary action. The absorbent zone should also be capable of absorbing a substantial volume of fluid that is equivalent to or greater than the total volume capacity of the material itself, and thus have a high absorbent capacity. Para. 0057.
See Chan in paragraph 0074 disclosing that the porous material or membrane in the reaction zone can be nitrocellulose.
While Chan teaches that the porous material membrane in the reaction zone can be nitrocellulose, Chan is silent as to the porous material or nitrocellulose contains pores of 0.2 um. However these are parameters of a known limitation (of the porous membrane) and appear to fall within a workable or optimum range. Where the general conditions of a claim are disclosed, such as here, discovering a workable or optimum range of parameters of the invention (in this case, the pore size as recited) requires routine skills in the art.
Chan also discloses a capture agent immobilized on or within the membrane member [see para. 0070 disclosing reaction zone 3 contains an immobilized capture reagent],
an absorbent pad member [see para. 0070 disclosing absorbent zone 4] having a first surface and a second surface, positioned under the membrane member, wherein the second surface of the membrane member and the first surface of the absorbent pad member are in contact with each other [see fig. 2];
and a holder [device 1, see figures 1 and 2 for example] with a first wall and a second wall, wherein: the first wall is positioned proximal to the first surface of the membrane member; the first wall has an opening traversing the first wall, the opening exposing a portion of the first surface of the membrane member to outside of the vertical flow assay device [see test device 1, test area 2 with an opening, reaction zone 3 and absorbent zone 4, in figures 1 and 2];
the second wall is positioned under the absorbent pad member [see figure 2, wherein a wall of the device 1 is under absorbent zone 4 (equivalent to Applicant’s absorbent pad member)];
and the holder [i.e., device 1] provides a tight-fit chamber in which the membrane member (3) and the absorbent pad member (4) are contained (see fig. 2).
Examiner notes that the device (1) appears to provide a tight-fit chamber for the membrane member (3) and absorbent pad member (4), see figure 2 wherein no space is shown between the elements. Alternatively, providing a tight-fit chamber for the membrane member and absorbent pad member results in a predictable outcome of maintaining the structure as well as allowing for fluid sample and reagents to flow vertically, as taught by Chan (see abstract and title regarding “vertical flow-through” diagnostic device.)
Moreover, Chan teaches that the composition of the reaction zone 3 and the immobilized capture reagent will be determined by the type of analyte being detection (para. 0070). Chan further teaches that since the apparatus is designed to be used in a method for detecting a target analyte, a capture reagent must be provided which will recognize and be capable of specifically binding to the target analyte (para. 0072). Chan teaches that examples of specific binding include antigens and antibodies, hormones and cell receptors, sugars and lectins (para. 0072).
However, Chan is silent as to an anti-IL-6 capture antibody, immobilized on or within at least one of the nitrocellulose membrane layers. However, the immobilized capture reagent will be determined by the type of analyte being detection, as taught by Chan (para. 0070).
Moreover, detecting IL-6 through its binding a capture is known in the art, as may be desirable for diagnostic purposes or research.
Kirkland teaches that the syndrome of septic shock is caused by over production of a host of inflammatory cytokines by monocytes and macrophages in response to microbial products. These include tumor necrosis factor (TNF)1, IL-1, IL-6, IL-8. Macrophages also secrete a wide variety of other compounds in response to microbial products…Production of all these mediators can culminate in hypotension, intravascular coagulation, poor organ perfusion, multi-organ failure and ultimately, death. Para. 0006.
Kirkland teaches that CD14 was tested for its ability to stimulate cells in the absence of LPS, and it was found to be inactive. In some experiments, U373 cells were stimulated with 1 ng/ml of human IL-1 b for 16 h. The concentration of IL-6 in the supernatants was determined by ELISA. For the ELISA assay, the IL-6 was captured with goat anti-human IL-6 neutralizing antibody and detected by rabbit anti IL-6. The rabbit antibody was detected with the goat anti-rabbit IgG-HRP. The color reaction was developed with and the OD [optical density] was measured. The amount of IL-6 was calculated compared to a standard curve of the recombinant human IL-6.
Para. 0135.
Given that the immobilized capture reagent on the Chan device will be determined by the type of analyte being detection, as taught by Chan (para. 0070), and that Kirkland teaches use of anti-IL-6 antibody to detect IL-6 for study, it would have been obvious to one skilled in the art that the anti-IL-6 antibody can be immobilized on the Chan device.
Applicant’s claim 2 recites that the membrane member comprises one or more porous solid state materials selected from one or more of plastic, polymers, paper, nitrocellulose, cellulose, PVDF, polycarbonate, ceramic, metallic materials, glass, glass microfibers, and anodized aluminum.
See Chan in paragraph 0074 disclosing that the porous material or membrane in the reaction zone can be nitrocellulose.
Applicant’s claim 3 recites that the membrane member comprises a nitrocellulose membrane.
See Chan in paragraph 0074 disclosing that the porous material or membrane in the reaction zone can be nitrocellulose.
Applicant’s claim 4 recites that the membrane member contains pores of 10 um or less in size and has a porosity of between 100% and 95%.
While Chan teaches that the porous material membrane in the reaction zone can be nitrocellulose, Chan is silent as to the porous material or nitrocellulose contains pores of 10 um or less in size and has a porosity of between 100% and 95%. However these are parameters of a known limitation (of the porous membrane) and appear to fall within a workable or optimum range. Where the general conditions of a claim are disclosed, such as here, discovering a workable or optimum range of parameters of the invention (in this case, the pore size and porosity as recited) requires routine skills in the art.
Applicant’s claim 5 recites that the membrane member comprises pores that are about 0.2 m in size. Where the general conditions of a claim are disclosed, such as here, discovering a workable or optimum range of parameters of the invention (in this case, the pore size as recited) requires routine skills in the art.
Applicant’s claim 6 recites that the absorbent pad member comprises one or more absorbent pads. See absorbent zone with absorbent pad membrane 4, for example, in figure 2.
Applicant’s claim 7 recites that the absorbent pad member contains pores ranging from between 1 m to 1000 m in size, and has thickness of between 1mm to 10 mm at 53 kPa.
Where the general conditions of a claim are disclosed, such as here, discovering a workable or optimum range of parameters of the invention (in this case, the pore size and thickness as recited) requires routine skills in the art.
Applicant’s claim 9 recites that the holder comprises a fitting configured to mount the vertical flow assay device onto a detection system [see detector in para. 0042, and detector 23 in para. 0112], and a portion of the membrane member can be accessed through the opening of the first wall of the holder to provide [capable of providing] a detectable signal indicative of the presence of the amount of IL-6 to the detection system [ see figs. 1 and 2].
Applicant’s claim 10 recites that the detection system is an imager, a scanner, or a smartphone. See paragraph 0112 of Chan disclosing that detector 23 can detect fluorescent material. Examiner notes that detector 23 is equivalent to a scanner.
Applicant’s claim 11 recites that the sample is a body fluid sample. See Chan in paragraph 0063 disclosing whole blood, plasma, serum, urine, saliva etc. as the fluid test sample.
Applicant’s claim 12 recites that the sample is a serum sample. See Chan in paragraph 0063 disclosing serum as the fluid test sample.
Applicant’s claim 13 recites that the device is disposable. Examiner notes that the Chan device may be disposed of, and therefore is considered to be disposable [an intended use.]
Claim(s) 8 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 20150285793 (hereinafter “Chan”) in view of US 20030114377 (hereinafter “Kirkland”), and further in view of US 20020164811 (hereinafter “Hud”).
Chan and Kirkland, discussed above, is silent as to the absorbent pad member comprising one or more absorbent pads made of cotton linter material, as recited in the present claim 8.
Chan does disclose that concentration of the sample through a reaction zone 3 can be achieved by having an absorbent material, or pad, beneath the reaction zone 3 that draws the sample, which is added to the surface of the reaction zone, through to the absorbent material below. The absorbent zone 4 can be generated from any material capable of wicking fluid by way of capillary action, such as cotton or paper.
Moreover, Hud teaches that cotton linter is known in the assay art for forming a porous membrane.
Specifically, Hud teaches that a solid support which contains four sequentially conjoined porous membrane areas consisting of: a sample application pad, a glycated hemoglobin binding membrane, a nonglycated hemoglobin binding membrane and a buffer flow wicking membrane. The application pad which is employed in the assay is generally a filter paper, with a synthetic polymer grade filter paper giving exceptionally good results. Although synthetic polymer grade paper is a preferred material for producing the application pad, it is to be understood that other materials may also be employed for producing such application pads including but not limited to cellulose acetate, rayon, cotton linter, nylon, PVDF, glass fiber and nitrocellulose. The glycated hemoglobin binding membrane which is employed in the assay is generally a porous material derivatized with glycated hemoglobin binding molecules. Activated cotton linter paper is a preferred material for the glycated hemoglobin binding membrane. Para. 0015.
Given that Chan teaches that the absorbent zone 4 can be generated from any material capable of wicking fluid by way of capillary action, such as cotton or paper, and Hud teaches that cotton linter is known in the assay art for forming a porous membrane, use of cotton linter as the absorbent zone would have been obvious to one skilled in the art as an alternative material.
Claim 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over US 20150285793 (hereinafter “Chan”) in view of US 20030114377 (hereinafter “Kirkland”) and further in view of
CA 3132566 (hereinafter “Umapathy”).
Applicant’s claim 20 recites a kit for detecting presence or an amount of interleukin 6 (IL-6) in a sample, comprising:
a vertical flow assay device of claim 1;
an anti-IL-6 capture antibody and a biotinylated anti-IL-6 detection antibody that each bind to IL-6;
a signal development element that can bind to the detection reagent;
a washing buffer;
a blocking buffer;
at least three spatially distinct reference zones configured to provide different predetermined reference signal intensities for semi-quantitative determination of IL-6 based on comparison of a test-zone signal with a reference-zone signal; and/or instructions for use.
As discussed above (see discussion of claim 1), Chan discloses a vertical flow assay device (1), a capture reagent (immobilized capture reagent, para. 0070), and a signal development element (indicator reagents or detectable substance, para. 0094) that can bind to the detection reagent (e.g., antibody, para. 0094).
Antibodies materials may also be labeled with colloidal particles, fluorescent markers or chemi-luminescent molecules according to the invention and used in sandwich type assays for the detection of antigen analytes or in competition assays for the detection of antibody analytes. Para. 0060.
Moreover, Chan further teaches the following.
Chan teaches that the porous material or membrane in the reaction zone can be treated with a blocking composition that prevents the target analyte and other components of the sample from non-specifically binding to the reaction zone (para. 0074). The blocking composition is equivalent to the recited blocking buffer.
Chan further teaches use of indicator reagents to detect the presence of a target analyte in a test sample (para. 0094). Cha also teaches a control molecule in the reaction zone, wherein color development at the test site may be compared with the color of one or more standard controls to determine whether the reagents are stable and the test is performing properly (para. 0073). The indicator marker, or alternatively, the control molecule, is equivalent to the recited calibration marker, in general.
Chan also discloses a liberated reagent to flow to resolubilize the indicator reagent (see paras. 0014 and 0043) . This reagent is equivalent to a wash, and it would have been predictable to one skilled in the art that the was may be a buffer, as well known in the assay art.
As to Applicants recitation of “at least three spatially distinct reference zones configured to provide different predetermined reference signal intensities for semi-quantitative determination of IL-6 based on comparison of a test-zone signal with a reference-zone signal; and/or instructions for use”,
Chan is silent as to at least three spatially distinct reference zones configured to provide different predetermined reference signal intensities for semi-quantitative determination of IL-6 based on comparison of a test-zone signal with a reference-zone signal; and/or instructions for use.
Chan does discloses the following.
In addition to the capture reagent, a defined area of the exposed reaction zone may also contain a control molecule. In this regard, color development at the test site may be compared with the color of one or more standards controls to determine whether the reagents are stable and the test is performing properly. In general, when testing for the presence of target analyte, the diagnostic device will have a built-in control of an antibody directed to human immunoglobulin G (IgG), IgM, IgE, or IgA. Thus when a fluid test sample is added to the diagnostic device, immunoglobulin will bind to the control region regardless of whether or not target analyte happens to be present in the sample. For example, a suitable control may be established by using Protein A which is disclosed in U.S. Pat. No. 5,541,059 (Chu). Other suitable controls are well known in the art. Para. 0073.
Moreover, Umapathy discloses the following.
An aspect of the invention provides a microfluidic device comprising:
at least one patterned, porous and hydrophilic layer patterned with wax outlining patterns to create hydrophobic barriers, at least one application zone for receiving a biological sample and a reagent; and optionally, at least one microfluidic channel for delivery of the biological sample and the reagent to a reaction zone, wherein said device is configured for detecting 5a-pregnan-3a-o1-20-one antigen at a concentration greater than 400 nanograms per gram in the biological sample. Page 3, lines 17-24.
Another aspect of the invention provides a microfluidic device, wherein said device
is a single-layer paper device (100) having three circular zones configured to receive a biological sample and a reagent, comprising:
a. a test zone (101) comprising immobilized 5a-pregnan-3a-o1-20-one antigen for colorimetric detection of 5a-pregnan-3a-o1-20-one;
b. a positive control zone (102) comprising immobilized 5a-pregnan-3a-o1-20-one antigen for colorimetric detection of 5a-pregnan-3a-o1-20-one;
c. a negative control zone (103); and
d. a wax pattern (104) on the paper layer, wherein the wax pattern outlines the test zone, the positive control zone and the negative control zone to create a hydrophobic barrier. Page 3, line 24 to page 4, line 8.
Yet another aspect of the invention provides a microfluidic device, wherein said device is a multi-layer device (200) comprising:
a. a first layer (300) configured for receiving a biological sample and reagents;
b. a second layer (400) configured for delivery of the biological sample and the reagents to a reaction zone;
c. a third layer (500) configured for delivery of the biological sample to the reaction zone; and
d. a fourth layer (600) configured for colorimetric detection of 5a-pregnan-3a-I-20-one. Page 4, line 9-17.
It would have been obvious to one skilled in the art to provide in the Chan device at least three spatially distinct reference zones [or three zones such as disclosed by Umapathy] in order to provide for controls as taught by Umapathy.
Response to Arguments
Applicant's arguments have been fully considered but they are not persuasive. Applicant has amended the recitation of the capture agent to recite an antibody. However, such limitations lack written description for the reasons set forth above. Applicant has also amended claim 20, but such limitations are taught by Umapathy.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Ann Montgomery whose telephone number is (571)272-0894. The examiner can normally be reached Mon-Fri, 9-5:30 PM PST.
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/Ann Montgomery/Primary Examiner, Art Unit 1678
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