`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`
`
`
`
`Civil Action No. 2:13-cv-04507
`CCC-MF
`
`
`
`
`
`Civil Action No. 2:13-cv-06929
`CCC-MF
`
`
`
`
`Civil Action No. 2:13-cv-07803
`CCC-MF
`
`
`JANSSEN PHARMACEUTICALS, INC.
`and GRÜNENTHAL GMBH,
`Plaintiffs/Counterclaim
`Defendants,
`
`v.
`ACTAVIS ELIZABETH LLC and ALKEM
`LABORATORIES LIMITED,
`Defendants/Counterclaim
`Plaintiffs.
`
`JANSSEN PHARMACEUTICALS, INC.
`and GRÜNENTHAL GMBH,
`Plaintiffs/Counterclaim
`Defendants,
`
`v.
`ROXANE LABORATORIES, INC.,
`Defendant/Counterclaim
`Plaintiff.
`
`JANSSEN PHARMACEUTICALS, INC.
`and GRÜNENTHAL GMBH,
`Plaintiffs/Counterclaim
`Defendants,
`
`v.
`ALKEM LABORATORIES LIMITED,
`Defendant/Counterclaim
`Plaintiff.
`
`
`
`
`
`DECLARATION OF JOEL BERNSTEIN, Ph.D.
`I, Joel Bernstein, Ph.D., hereby declare as follows:
`
`
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`Page 1 of 21
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`Grunenthal GmbH Exhibit 2006
`Rosellini v. Grunenthal GmbH
`IPR2016-00471
`
`
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`I.
`
`BACKGROUND AND QUALIFICATIONS
`1.
`I received a B.A. degree in chemistry from Cornell University in
`
`1962, and M.Sc. and Ph.D. degrees in chemistry from Yale University in 1964 and
`
`1967, respectively. Upon completing my Ph.D., I was a postdoctoral fellow for
`
`two years at the University of California in Los Angeles, and for two additional
`
`years at the Weizmann Institute of Science in Rehovot, Israel. My post doctoral
`
`work focused on the areas of organic solid state chemistry, polymorphism,
`
`chemical crystallography, properties of organic solids, and X-ray crystallography.
`
`Since 1967, I have used a variety of analytical techniques to study, characterize,
`
`and understand organic solids.
`
`2.
`
`Until my mandatory retirement in January 2010, I was a Professor of
`
`Chemistry and the Carol and Barry Kaye Chair in Applied Science at Ben-Gurion
`
`University of the Negev, Beer Sheva, Israel, where I had been a faculty member
`
`since 1971, and now am Professor Emeritus. From 2010 to 2013, I was Professor
`
`of Chemistry at New York University Abu Dhabi. My appointment since
`
`September 1, 2013 is Global Distinguished Professor of Chemistry at that
`
`institution. I have the same appointment at New York University Shanghai for the
`
`fall semester 2014.
`
`
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`2
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`3.
`
`I have taught and continue to teach courses in general chemistry,
`
`crystallography, and organic solid state chemistry, including polymorphism and
`
`crystallization.
`
`4.
`
`I have been, and continue to be, involved in professional organizations
`
`dealing with crystallography. I have twice been President of the Israel
`
`Crystallographic Society. I was Vice President of the European Crystallographic
`
`Association and Chairman of the Organizing Committee of the XIX Congress and
`
`General Assembly of the International Union of Crystallography held in 2002 in
`
`Geneva (with approximately 2,000 participants). I was a co-founder of the
`
`European Polymorphism Network, a consortium of European scientists active in all
`
`areas of polymorphism, which was created in 2001 under the auspices of the
`
`European Science Foundation. I was co-director of the NATO International
`
`Advanced School on Polymorphs and Solvates, which took place in Sicily in June
`
`2004.
`
`5.
`
`In 1999, I was elected a Fellow of the American Association for the
`
`Advancement of Science. I have engaged in industrial consulting in the areas of
`
`polymorphism of pharmaceuticals and solid state organic chemistry and
`
`crystallography for pharmaceutical companies such as Minnesota Mining and
`
`Manufacturing Co. (3M), GlaxoSmithKline PLC, Eli Lilly and Co., Pfizer, Inc.,
`
`Abbott Laboratories, AstraZeneca, and Sanofi-Aventis Pharmaceuticals.
`
`
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`6.
`
`I have published extensively on the topics of polymorphism,
`
`crystallography, and organic solid state chemistry, including refereed papers, book
`
`chapters, and reviews. I wrote a book entitled Polymorphism in Molecular
`
`Crystals, which was published by Oxford University Press in 2002 and translated
`
`into Russian in 2008. My curriculum vitae is attached as Exhibit A, and it lists my
`
`approximately 190 scientific publications, most of which deal with these topics.
`
`7.
`
`I have been retained by Sidley Austin LLP on behalf of Janssen
`
`Pharmaceuticals, Inc. to testify in this litigation as an expert witness in the areas of
`
`organic solid state chemistry, crystal chemistry, crystallography, and
`
`polymorphism.
`
`8.
`
`I was asked to review U.S. Patent No. 7,994,364 ("the '364 patent")1
`
`and the correspondence between the patent applicants and the United States Patent
`
`and Trademark Office that resulted in the patent (referred to as the "prosecution
`
`history") and provide an opinion concerning how a person of ordinary skill in the
`
`art would have understood the terms "X-ray pattern (2-theta values) in a powder
`
`diffraction when measured using CuKα radiation essentially the same as that
`
`provided in FIG. 1" and "monoclinic form" as used in the patent claims.
`
`9.
`
`The opinions below are based on my background and experience
`
`including more than 45 years of professional and educational experience in the
`
`1 The '364 patent is attached as Exhibit 2 to the Declaration of S. Isaac Olson
`("Olson Decl.")
`
`
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`4
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`study, characterization, and analysis of organic solids, the documents cited herein,
`
`and the information available to me to date.
`
`II. LEGAL PRINCIPLES OF WHICH I HAVE BEEN INFORMED
`10.
`I am not a lawyer, but I have been informed by counsel that when the
`
`words of a patent claim are not expressly defined in the patent specification, they
`
`are generally given their ordinary and customary meaning to a "person of ordinary
`
`skill" in the relevant discipline at the time of the invention. I have also been
`
`informed that such a person of ordinary skill is deemed to have read the entire
`
`patent and prosecution history, and that the ordinary and customary meaning to
`
`such a person must be determined in the context of the entire patent and
`
`prosecution history.
`
`11.
`
`I have not been asked to define the exact level of skill of a person of
`
`ordinary skill in the art, but I believe that such a person would have a working
`
`knowledge of crystallography.
`
`12.
`
`I have also been told that for purposes of claim construction, the focus
`
`is on how a person of ordinary skill in the relevant field would have understood the
`
`claim terms—in light of the '364 patent and its prosecution history—as of June
`
`2004, the earliest effective filing date of the '364 patent.
`
`13.
`
`I base my opinion on my review of the '364 patent and its prosecution
`
`history and on my knowledge of crystallography as of June 2004.
`
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`III. SUMMARY OF OPINIONS
`14. A person of ordinary skill in the art would have understood that "X-
`
`ray pattern (2-theta values) in a powder diffraction when measured using CuKα
`
`radiation essentially the same as that provided in FIG. 1," as used in the context of
`
`claim 3 of the '364 patent, had its plain meaning in the field of crystallography. In
`
`June 2004, a person of ordinary skill in the art would have understood that the
`
`plain meaning of this phrase would be an X-ray pattern that was essentially the
`
`same as Figure 1, even if, for example, the relative intensity of the peaks was
`
`different, there was peak broadening, and there were slight differences in peak
`
`positions.
`
`15. Furthermore, a person of ordinary skill in the art would have
`
`understood that "monoclinic form," as used in the context of claim 4 of the '364
`
`patent, had its plain meaning in the field of crystallography as described in the
`
`scientific literature. See, e.g., J. Glusker & K. Trueblood, Crystal Structure
`
`Analysis: A Primer 232 (Oxford University Press 1985) ("monoclinic form"
`
`means "[a] unit cell in which there is a two-fold rotation axis parallel to one cell
`
`axis (usually chosen as b)."), attached as Exhibit B. Such a plain meaning would
`
`not include specific numerical parameters for the elemental cell length of side and
`
`angles.
`
`
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`IV. TUTORIAL
`A. Crystals
`16. Crystals are solids in which the atoms (or molecules) are arranged in a
`
`periodic repeating pattern that extends in three dimensions, somewhat like the
`
`bricks in a brick wall or the paving stones in an old street. When crystals are
`
`grown slowly and carefully, they are often bounded by plane faces (flat surfaces
`
`extending in different directions) that can be seen with the naked eye. Looking at
`
`table salt under a microscope will often reveal these plane faces. Plane faces can
`
`also be seen in the beautiful mineral samples that are displayed in many museums.
`
`17. The internal structure or framework of a crystal (called the crystal
`
`structure) is determined by the position of the molecules relative to each other and
`
`extending in three dimensions. Knowing the internal framework of a crystal
`
`allows one to construct a three-dimensional model of the crystal with all molecules
`
`in the correct location relative to each other. If one thinks of crystals in a
`
`geometric sense, a concept known as a space lattice can be used to represent the
`
`crystal. The space lattice is like graph paper with repeating units but extending in
`
`three dimensions. The intersections of the lines making up the repeating units are
`
`points of the lattice. A simple example of a space lattice is shown below.
`
`
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`
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`18. The smallest volume element that is repeated in the three dimensions
`
`of crystalline solids is known as the unit cell (or elemental cell). The network of
`
`lines through the points of the space lattice divides it into unit cells. Thus, for
`
`example, if one thinks of a crystal structure as a brick wall, the unit cell would be
`
`analogous to a single brick in that brick wall.
`
`19. There are seven known crystal systems or forms, best classified in
`
`terms of their symmetry. They are the triclinic, monoclinic, orthorhombic,
`
`tetragonal, cubic, trigonal, and hexagonal forms. Each of these forms has a unit
`
`cell with a distinct fundamental shape. See, e.g., International Tables for X-Ray
`
`Crystallography, Table 2.3.1, p. 11 (1969), attached as Exhibit C.
`
`20. An example of a simple cubic unit cell, for example, is shown below.
`
`
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`The unit cell can be described by (1) a set of coordinate lattice axes—a, b, and c—
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`which originate at one of the lattice points and that form edges of the unit cell, and
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`(2) the intersecting angles of those axes—alpha (α), beta (β), and gamma (γ).
`
`These lengths and angles are known as lattice parameters, and for the simple cubic
`
`unit cell above, by symmetry a = b = c and α = β = γ = 90°.
`
`B.
`Polymorphs
`21. Although the order displayed by molecules in a crystal is
`
`characteristic of a crystalline form, a given chemical species may crystallize in
`
`more than one crystal structure. This is called polymorphism.2 Because the
`
`properties of a solid material depend in part on its crystalline form, polymorphic
`
`structures of the same compound can and often do exhibit different chemical,
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`physical, and biological properties. For example, properties such as hardness,
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`density, electrical conductivity, and shape can vary between different polymorphs.
`
`Other properties that normally vary between polymorphs of a given substance
`
`include solubility, dissolution rate, and vapor pressure, among others. In the
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`pharmaceutical industry, the fact that compounds of interest have multiple
`
`polymorphs can be of great significance, particularly because the different
`
`2 Materials may also crystallize along with water, the result being a hydrate, or
`along with a solvent, the result being a solvate. These can also exhibit different
`structures, or polymorphism. An amorphous solid, exhibiting no long range order,
`may also be formed. Very often among practitioners involved in this crystal
`chemistry the term polymorphism is used generically to include all of these
`possibilities.
`
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`polymorphs may have significantly different chemical and physical characteristics,
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`which may affect the manufacturability, performance, and/or quality of any
`
`ultimate drug product.
`
`22. Carbon is an example of a chemical species which can form
`
`polymorphs.3 Carbon can crystallize as graphite (the "lead" in a pencil) or as
`
`diamond. These two crystalline forms differ in properties such as hardness,
`
`density, electrical conductivity, and shape. Graphite and diamonds can coexist at
`
`room temperature, although the thermodynamically more stable form is graphite.
`
`These significant differences in properties, brought about by differences in crystal
`
`structure, are not unique to carbon; they occur in other materials that display
`
`polymorphism.
`
`23. The lattice parameters of a crystalline structure are unique and can be
`
`used to distinguish one crystalline form, i.e., polymorph, of a molecule from
`
`another.
`
`C. X-ray Powder Diffraction ("XRPD")
`24. X-ray powder diffraction (also called powder X-ray diffraction,
`
`PXRD, or XRPD) is a technique used to identify crystals and to determine crystal
`
`structure. In the pharmaceutical industry, XRPD is the most commonly used
`
`method of X-ray analysis for identifying solid forms, including polymorphs.
`
`3 When polymorphism occurs in an element, as is the case here, it is often referred
`to as allotropism.
`
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`25. When X-rays interact with a crystalline substance, the X-rays will be
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`scattered by the electrons of the atoms of the crystalline structure. As a result of
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`this scattering, the X-rays travel in well-defined beams in a few directions. This
`
`phenomenon is referred to as diffraction.
`
`26. This scattering of X-rays can be detected and measured. Every
`
`crystalline substance gives a diffraction pattern characteristic of that solid. Thus,
`
`the X-ray diffraction pattern of a pure crystal is analogous to a fingerprint of that
`
`solid; it is unique in the same way that a human fingerprint is unique. The X-ray
`
`diffraction pattern contains information on the arrangement of the atoms (or
`
`molecules) of the chemical species in the crystalline state. The X-ray powder
`
`diffraction pattern may be reported either in graphical form with the intensity (on
`
`the y axis) as a function of the diffraction angle (on the x axis), or as a numerical
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`listing of one or more identifying peaks (d-spacing or 2θ values versus relative
`
`intensity). In the chemical literature it is not uncommon to find solid compounds
`
`identified by the listing of X-ray diffraction peaks or patterns because the XRPD
`
`pattern produced by a particular crystal form of a compound is unique to that
`
`crystal form.
`
`27. To obtain an XRPD, crystal samples are mounted on a device and
`
`exposed to incident X-rays from an X-ray source. In the examples of the '364
`
`patent, a copper X-ray tube was used as the source of a specific type of X-ray –
`
`
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`11
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`CuKα radiation. '364 patent at col. 8, ll. 10-13. This type of radiation is
`
`commonly used for XRPD, but other radiation sources were available in June
`
`2004. Using a different radiation source would change the scale along the x-axis
`
`because X-rays of different wavelengths would be employed. But the overall
`
`pattern would remain unchanged. As the X-rays pass through the crystal sample at
`
`different angles, the crystal sample diffracts the incident X-ray beam. The
`
`diffracted X-rays are measured as a function of the incident angle, called the
`
`"Bragg" angle.4 Each lattice plane within the crystal will diffract incident rays
`
`differently.
`
`28. The XRPD plot is often recorded as measurements of "relative"
`
`intensity (relative to the strongest reflection which is given an arbitrary value of
`
`100 on the vertical axis) plotted against the recorded angle of diffraction
`
`(horizontal axis). The recorded angle of diffraction is often referred to as "2θ"
`
`(which is pronounced "two theta"). This pattern of peaks can be used to identify
`
`the material in the sample.
`
`29. Acceptable experimental error in the measurement of XRPD
`
`diffraction angles is ±0.20 degrees. See The United States Pharmacopeia, (method
`
`
`4 Either the sample or the radiation source can move. When the sample is moved
`during detection, the radiation source remains stationary and the detector moves
`simultaneously with the sample at the same rate of speed. When the sample
`remains stationary, the X-ray source and the detector move simultaneously at the
`same rate of speed.
`
`
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`12
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`<941>), 2233-34, (26th rev. 2003), attached as Exhibit D. The ±0.20 degree
`
`magnitude of error is referred to in the patent specification. '364 patent at col. 2, ll.
`
`14-36 and claim 1.
`
`30. An unknown crystalline material can be identified by comparing its
`
`X-ray powder diffraction pattern with those of a reference material or standard.
`
`See The United States Pharmacopeia, Exh. D at 2234. Although the y-axis relative
`
`peak intensities for a test sample and a reference standard can vary considerably
`
`and still be considered a match, the agreement between the x-axis location of the
`
`peaks (2θ values) should be within the calibrated precision of the diffractometer for
`
`diffraction angle, which will typically be ±0.20 degrees if the samples contain the
`
`same crystalline material. Id.
`
`V. THE '364 PATENT
`31. The '364 patent describes the discovery of a new polymorphic,
`
`crystalline form, Form A, of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-
`
`methylpropyl)-phenol hydrochloride. The '364 patent states that the new
`
`crystalline form A can be identified by X-ray powder diffraction and that the
`
`XRPD pattern for Form A is shown in Figure 1. See, e.g., '364 patent at col. 2, ll.
`
`14-19. Example 10 of the '364 patent describes how the XRPD pattern shown in
`
`Figure 1 was obtained and also contains a listing of some of the XRPD peaks for
`
`Form A. '364 patent at col. 8, ll. 1-52.
`
`
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`32. As explained in the '364 patent, the single crystal structure analysis of
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`Form A of (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol
`
`hydrochloride determined that the crystal of Form A is monoclinic. See, e.g., '364
`
`patent at col. 2, ll. 54-64; Example 12 including col. 10, l. 38-41. The '364 patent
`
`does not specifically provide a definition for the term "monoclinic."
`
`VI.
`
`INTERPRETATION OF THE CLAIM LANGUAGE
`A.
`
`"X-ray pattern (2-theta values) in a powder diffraction when
`measured using CuKα radiation essentially the same as that
`provided in FIG. 1."
`I have been told that Plaintiffs and Defendants disagree about the
`
`33.
`
`meaning of the language "X-ray pattern (2-theta values) in a powder diffraction
`
`when measured using CuKα radiation essentially the same as that provided in FIG.
`
`1" as used in claim 3 of the '364 patent. Claim 3 states:
`
`3. The crystalline Form A of (-)-(1R,2R)-3-(3-
`dimethylamino-1-ethyl-2-methylpropyl)-phenol
`hydrochloride according to claim 1 exhibiting an X-ray
`pattern (2-theta values) in a powder diffraction when
`measured using CuKα radiation essentially the same as
`that provided in FIG. 1.
`
`34. After reviewing the specification and claims of the '364 patent, as well
`
`as its prosecution history, a person of ordinary skill in the art would have
`
`understood that "X-ray pattern (2-theta values) in a powder diffraction when
`
`measured using CuKα radiation essentially the same as that provided in FIG. 1," as
`
`used in claim 3 of the '364 patent, has the plain meaning that this language would
`
`
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`have had to a person with a working knowledge of crystallography. In June 2004,
`
`such a person would have understood that an X-ray pattern for a test sample would
`
`be considered a match to a reference standard if the two patterns were essentially
`
`the same. This could be true even where the relative intensity of the peaks were
`
`different, where there was peak broadening, and there were slight differences in
`
`peak positions, so long as the pattern indicates the same material is present. Such a
`
`person would have experience in recognizing the patterns that distinguish one
`
`polymorphic form from a different polymorphic form of the same solid, or for that
`
`matter, that distinguish two entirely unrelated solids.
`
`35. Two of the figures from the '364 patent, Figures 1 and 7, are
`
`reproduced below.
`
`
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`In determining whether another XRPD pattern is "essentially the same
`
`36.
`
`as that provided in FIG. 1," a person of ordinary skill in the art would visually
`
`compare the peak positions on the x-axis for the two XRPD patterns. For there to
`
`be a match, the peak positions could vary in location by ± 0.2 degrees even where
`
`the same machine and radiation type were used. The specification of the '364
`
`patent notes this range of error. See '364 patent, Claim 1 and col. 2, ll. 14-36
`
`(reciting ± 0.2 for each peak location); see also The United States Pharmacopeia,
`
`Exh. D at 2234.
`
`37. Factors such as temperature, preferred orientation and non-uniform
`
`particle size can impact the relative intensity of peaks from two samples of the
`
`same crystalline material. As a result, there could be a match even if the relative
`
`intensities of the peaks (i.e., the height of the peaks on the y-axis) in the two XRPD
`
`patterns varied considerably. See The United States Pharmacopeia, Exh. D at
`
`
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`2234. In other words, for there to be a match, the two XRPD patterns need not
`
`have peak heights that are exactly the same. The relative ratio of peak heights may
`
`also differ.
`
`38. A person of ordinary skill in the art also would have understood that
`
`for there to be a match, the peaks in one pattern may be broader or narrower than
`
`the peaks in another pattern. For instance, differences between instruments and
`
`their settings, differences in experimental design, or imperfections in the crystal
`
`sample can contribute to peak broadening.
`
`39. Broadening contributions from the instrument can arise from factors
`
`such as differences in the source of radiation or wavelength of the incident X-rays,
`
`monochromatization of the radiation, as well as possible misalignment of the
`
`diffractometer. Thus, one XRPD diffractometer may produce XRPD patterns with
`
`broader peaks than another XRPD diffractometer.
`
`40. Broadening contributions from the crystal sample can arise from
`
`factors such as the particle size in the prepared crystal sample and/or mosaic spread
`
`in the crystal lattice. Mosaic spread means that unit cells in a crystal are not
`
`always perfectly aligned. That imperfect alignment may cause differences in the
`
`angles at which X-rays will diffract that can result in a broadening of some or all of
`
`the peaks. Differences in particle size in the prepared crystal sample also may
`
`introduce non-uniformities in the sample which can contribute to peak broadening.
`
`
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`41.
`
`In addition, the presence of impurities or additional ingredients in a
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`sample containing a crystal could result in the appearance of peak broadening if,
`
`for example, extraneous peaks from the impurities or other ingredients in the
`
`sample overlap with peaks from the crystal.
`
`42.
`
`I understand that Defendant Alkem has proposed a construction for
`
`"essentially the same as." Alkem's construction is "having essentially the same
`
`peak locations and intensities." I disagree with that construction. As discussed
`
`above, a person of ordinary skill would have understood that there could be a
`
`match even if the location of the peaks of the test sample differed from those of the
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`reference standard. Indeed, the specification of the '364 patent notes a range of
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`error of ±0.2. A person of ordinary skill would also have understood that there
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`could be a match even if the intensities of those peaks varied considerably. For
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`example, in the literature many solids are identified only by some (not all) peak
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`positions. In June 2004, those of ordinary skill in the art were trained and
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`accustomed to comparing XRPD patterns to evaluate similarities and differences.
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`As a result, the claim should not be limited to "essentially the same peak positions
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`and intensities" as Alkem proposes because the skilled artisan's pattern recognition
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`abilities involved more than these two parameters.
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`Case 2:13-cv-04507-CCC-MF Document 141-24 Filed 08/08/14 Page 19 of 21 PageID: 2944
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`B.
`43.
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`"monoclinic form"
`I have also been told that Plaintiffs and Defendants disagree about the
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`meaning of the term "monoclinic form" as it appears in claim 4 of the '364 patent.
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`Claim 4 states:
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`4. The crystalline Form A of (-)-(1R,2R)-3-(3-
`dimethylamino-1-ethyl-2-methylpropyl)-phenol
`hydrochloride according to claim 1 wherein the crystal
`has a monoclinic form.
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`44. The '364 patent uses, but does not define, the term "monoclinic form."
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`After reading the specification, claims, and prosecution history, a person of
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`ordinary skill in the art in June 2004 would have understood that "monoclinic
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`form" as used in Claim 4 of the '364 patent had its plain and ordinary meaning in
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`the field of crystallography. This meaning was described in the scientific
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`literature. See, e.g., J. Glusker & K. Trueblood, Exh. B at 232 ("[a] unit cell in
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`which there is a two-fold rotation axis parallel to one cell axis (usually chosen as
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`b).").
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`45. An example of a simple monoclinic unit cell is shown below, together
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`with (on the right) a labeling scheme for describing the dimensions of a cell.
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`46. The '364 patent does not provide any special definition of "monoclinic
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`form." Nothing in the '364 patent suggests that "monoclinic form" was used to
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`mean something different from its plain meaning in June 2004 in the field of
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`crystallography. See, e.g., '364 patent, Example 12.
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`47.
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`I understand that Defendants Alkem and Roxane have proposed a
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`construction of "monoclinic form" as follows: a "form having the following
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`parameters of the elemental cell (length of side and angle): a: 7.11 Å, b: 11.62 Å,
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`c: 17.43 Å, β: 95.0°." I disagree with Defendants' construction. Nothing in the
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`claim language limits "monoclinic form" to the specific unit cell parameters recited
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`by Defendants. Although this could easily have been done, no such limitations
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`appear in claim 4.
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`48. To be sure, the numerical parameters relied upon by Alkem and
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`Roxane are listed in Example 12 of the '364 patent (see col. 10, Table 3). But a
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`person of ordinary skill in the art would have understood that the broad term
`
`"monoclinic form" was not limited to the specific numerical parameters listed in
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`
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